Oxyiminoalkanoic acid derivatives

ABSTRACT

A compound represented by the formula:                    
     wherein R 1  is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)— or a group represented by —NR 6 — wherein R 6  is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, —SO—, —SO 2 — or a group represented by —NR 7 — wherein R 7  is a hydrogen atom or an optionally alkyl group; ring A is a benzene ring optionally having additional one to three substituents; p is an integer of 1 to 8; R 2  is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R 3  is a hydroxy group, OR 8  (R 8  is an optionally substituted hydrocarbon group.) or NR 9 R 10  (R 9  and R 10  are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R 9  and R 10  combine together to form a ring); R 4  and R 5  are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R 4  may form a ring with R 2 ; provided that when R 1  is a ethoxymethyl, a C 1-3  alkyl, phenyl or p-methoxyphenyl and q=m=0, R 3  is NR 9 R 10 ; and provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime and a methyl pyruvate of [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxypropionic acid are excluded; or a salt thereof which has excellent hypoglycemic and hypolipidemic actions.

This application is a divisional application from U.S. patentapplication Ser. No. 09/423,854, filed Nov. 15, 1999 now issued U.S.Pat. No. 6,251,926; which was the National Stage of InternationalApplication No. PCT/JP99/02407, filed on May 10, 1999.

TECHNICAL FIELD

The present invention relates to novel oxyiminoalkanoic acid derivativeshaving hypoglycemic effect and hypolipidemic effect, a novelpharmaceutical composition and retinoid-related receptor functionadjuster comprising an oxyiminoalkanoic acid. Such noveloxyiminoalkanoic acid derivatives, pharmaceutical compositions andretinoid-related receptor function adjusters are useful as an agent forprevention and/or treatment of diabetes mellitus, hyperlipemia, impairedglucose tolerance, inflammatory disease, arteriosclerosis and the like.

BACKGROUND ART

Examples of known oxyiminoalkanoic acid derivatives are theintermediates used in the production of β-lactam compounds (JapanesePatent Application KOKAI No. 49382/1983, 167576/1984, 77391/1987,192387/1987, 47186/1991) and a compound having a leukotrienebiosynthesis inhibiting effect (e.g., WO96/02507).

However, these compounds have not been reported to have hypoglycemic,hypolipidemic effects and retinoid-related receptor function adjusteractivity yet.

On the other hand, oxime derivatives were reported as a prophylacticand/or therapeutic agent against hyperlipemia and hyperglycemia (e.g.,Japanese Patent Application KOKAI No. 48779/1997, 323929/1997), butthese derivatives are not an oxyiminoalkanoic acid derivative.

Moreover, while a phenylalkanoyl acid derivative having a substitutedhydroxyl group on its 4-position is reported (e.g. in WO97/31907,WO97/25042) as a peroxisome proliferator-activated receptor gamma(abbreviated occasionally as PPARγ in this specification) agonist whichis one of retinoid-related receptor function adjusters, this derivativeis not an oxyiminoalkanoic acid derivative.

The peroxisome proliferator-activated receptor gamma (PPARγ) is a memberof an intranuclear hormone receptor superfamily, representatives ofwhich are a steroid hormone receptor and a thyroidal hormone receptor,and induced to be expressed at a very early stage of the fat celldifferentiation, and plays an important role as a master regulator inthe fat cell differentiation. PPARγ is bound to a function adjuster toform a dimer with a retinoid X receptor (RXR), and is also bound to theresponding site of a target gene in a nucleus, whereby regulating(activating) the transcription efficiency directly. Recently, ametabolite of prostaglandin D₂, namely, 15-deoxy-Δ^(12,14) prostaglandinJ₂, was proved to be an endogenous agonist of PPARγ, and some insulinsensitivity enhancing agent, such as a thiazolindione derivative, wasproved to have a PPARγ agonistic activity, with its potency being inparallel with its blood sugar reducing effect and fat celldifferentiation promoting effect [Cell, Vol. 83, page 803 (1995); TheJournal of Biological Chemistry, Vol. 270, page 12953 (1995); Journal ofMedicinal Chemistry, Vol. 39, page 655 (1996)]. More recently, it hasbeen shows that: 1) PPARγ is expressed in a cultured, human fatsarcoma-derived cell, and its growth is terminated by addition of PPARγagonist [Proceedings of the National Academy of Science of The UnitedStates of America, Vol. 94, page 237 (1997)], 2) a non-steroidantiinflammatory agent such as indomethacin and phenoprofen has a PPARγagonistic activity [The Journal of Biological Chemistry, Vol. 272, page3406 (1997)], 3) PPARγ is highly expressed in an activated macrophage,and the addition of its agonist serves to inhibit the transcription of agene concerned in an inflammation [Nature, Vol. 391, p.79 (1998)], and4) a PPARγ agonist inhibits the production of inflammatory cytokines(TNF α, IL-1 β, IL-6) by a monocyte [Nature, Vol. 391, page 82 (1998)].

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a noveloxyiminoalkanoic acid derivative and retinoid-related receptor functionadjuster which has excellent hypoglycemic effect and hypolipidemiceffect and which is useful as an agent for prevention and/or treatmentof diabetes mellitus, hyperlipemia, impaired glucose tolerance, aninflammatory disease and an arteriosclerosis.

The present invention relates to:

1) a compound represented by Formula (I-1):

 wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)—or a group represented by —NR⁶— wherein R⁶ is a hydrogen atom or anoptionally substituted alkyl group; n is an integer of 1 to 3; Y is anoxygen atom, a sulfur atom, —SO—, —SO₂— or a group represented by —NR⁷—wherein R⁷ is a hydrogen atom or an optionally substituted alkyl group;a ring A is a benzene ring optionally having additional one to threesubstituents; p is an integer of 1 to 8; R² is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R³ is ahydroxy group, OR⁸ (R⁸ is an optionally substituted hydrocarbon group.)or NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group or R⁹ and R¹⁰ combine together to form a ring);R⁴ and R⁵ are the same or different groups which are selected from ahydrogen atom or an optionally substituted hydrocarbon group wherein R⁴may form a ring with R²; provided that when R¹ is a ethoxymethyl, a C₁₋₃alkyl, phenyl or p-methoxyphenyl and q=m=0, R³ is NR⁹R¹⁰; and providedthat O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime of methylpyruvate and[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxypropionic acid areexcluded; or a salt thereof;

2) A compound of the above 1) wherein R¹ is an optionally substitutedheterocyclic group or an optionally substituted cyclic hydrocarbongroup;

3) A compound of the above 1) wherein X is a bond or a group representedby —NR⁶— wherein R⁶ is an optionally substituted alkyl group;

4) A compound of the above 1) wherein n is 1 or 2;

5) A compound of the above 1) wherein Y is an oxygen atom;

6) A compound of the above 1) wherein p is an integer of 1 to 3;

7) A compound of the above 1) wherein R³ is a hydroxy group or —OR⁸ or—NR^(9′)R^(10′), wherein R⁸ is an optionally substituted hydrocarbongroup and R^(9′) and R^(10′) are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, or R^(9′) and R^(10′) combine together to form a ring;

8) A compound of the above 1) wherein q is an integer of 0 to 4;

9) A compound of the above 1) wherein R² an optionally substitutedhydrocarbon group;

10) A compound ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid or its salt;

11) A compound which is selected from a group ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramideandE-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoicacid;

12) A compound of the above 2) wherein a ring of an optionallysubstituted heterocyclic group or an optionally substituted cyclichydrocarbon group of R¹ is selected from the group represented byformulae of

13) A compound of the above 12) wherein the ring optionally has one ortwo substituents which is selected from the group of an optionallysubstituted phenyl, an optionally substituted furyl, an optionallysubstituted thienyl and an optionally substituted C₁₋₄ alkyl;

14) A compound of the above 12) wherein the ring is

 wherein Ph is an optionally substituted phenyl group, and R″ is ahydrogen or an optionally substituted C₁₋₆ alkyl group;

15) A compound represented by Formula (I-2) of

 wherein R′ is an optionally substituted phenyl, furyl or thienyl group;R″ is a hydrogen or a C₁₋₆ alkyl which is optionally substituted by atleast one selected from a group of a C₁₋₆ alkoxy and a halogen; R^(2′)is a phenyl which is optionally substituted by at least one selectedfrom a group of a hydrogen, an alkyl, an alkoxy and a halogen; q is aninteger of 1 to 6; and R^(3′) is a hydroxy, a C₁₋₆ alkoxy or —NR⁹R¹⁰ inwhich R⁹ and R¹⁰ are independently selected from the group of a hydrogenatom, an optionally substituted hydrocarbon group, an optionallysubstituted heterocyclic group or an optionally substituted acyl group,or R⁹ and R¹⁰ combine together to form a ring; a ring A is a benzenering optionally having additional one to three substituents; or a saltthereof;

16) A pharmaceutical composition comprising a compound represented byFormula (II)

 wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)—or a group represented by —NR⁶— wherein R⁶ is a hydrogen atom or anoptionally substituted alkyl group; n is an integer of 1 to 3; Y is anoxygen atom, a sulfur atom, —SO—, —SO₂— or a group represented by —NR⁷—wherein R⁷ is a hydrogen atom or an optionally substituted alkyl group;ring A is a benzene ring optionally having additional one to threesubstituents; p is an integer of 1 to 8; R² is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R³ is ahydroxy group, OR⁸ (R⁸ is an optionally substituted hydrocarbon group.)or NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group or R⁹ and R¹⁰ combine together to form a ring);R⁴ and R⁵ are the same or different groups which are selected from ahydrogen atom or an optionally substituted hydrocarbon group wherein R⁴may form a ring with R²; or a salt thereof;

17) A pharmaceutical composition of the above 16) which is a compositionfor prevention or treatment of diabetes mellitus;

18) A pharmaceutical composition of the above 16) which is a compositionfor prevention or treatment of hyperlipemia;

19) A pharmaceutical composition of the above 16) which is a compositionfor prevention or treatment of impaired glucose tolerance;

20) A pharmaceutical composition of the above 16) which is a compositionfor prevention or treatment of an inflammatory disease; and

21) A pharmaceutical composition of the above 16) which is a compositionfor prevention or treatment of an arteriosclerosis.

22) An agent for controlling or adjusting retinoid-related receptorcomprising a compound represented by Formula (II) of

 wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)—or a group represented by —NR⁶— wherein R⁶ is a hydrogen atom or anoptionally substituted alkyl group; n is an integer of 1 to 3; Y is anoxygen atom, a sulfur atom, —SO—, —SO₂— or a group represented by —NR⁷—wherein R⁷ is a hydrogen atom or an optionally substituted alkyl group;ring A is a benzene ring optionally having additional one to threesubstituents; p is an integer of 1 to 8; R² is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R³ is ahydroxy group, OR⁸ (R⁸ is an optionally substituted hydrocarbon group.)or NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group or R⁹ and R¹⁰ combine together to form a ring);R⁴ and R⁵ are the same or different groups which are selected from ahydrogen atom or an optionally substituted hydrocarbon group wherein R⁴may form a ring with R²; or a salt thereof;

23) An agent of the above 22) which is a ligand of a peroxisomeproliferator-activated receptors;

24) An agent of the above 22) which is a retinoid X receptor ligand;

25) An agent of the above 22) which is an insulin sensitivity enhancingagent;

26) An agent of the above 22) which is an insulin resistance improvingagent;

(1) Definition of R¹

A hydrocarbon group in “an optionally substituted hydrocarbon group”represented by R¹ in Formulae (I-1) and (II) includes an aliphatichydrocarbon group, an alicyclic hydrocarbon group, analicyclic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbongroup and an aromatic hydrocarbon group. The number of the carbon atomsin each of these hydrocarbon group is preferably 1 to 14.

(1-1) Definition of Hydrocarbon Group for R¹

As the aliphatic hydrocarbon group, an aliphatic hydrocarbon grouphaving 1 to 8 carbon atoms is preferred. Such aliphatic hydrocarbongroup includes a saturated aliphatic hydrocarbon group having 1 to 8carbon atoms (e.g., an alkyl group) such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, heptyl, octyl and the like; an unsaturatedaliphatic hydrocarbon group having 2 to 8 carbon atoms (e.g., an alkenylgroup, an alkadienyl group, an alkynyl group, an alkadiynyl group andthe like) such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl,5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl,2-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl,1-octynyl and the like.

As the alicyclic hydrocarbon group, an alicyclic hydrocarbon grouphaving 3 to 7 carbon atoms is preferred. Such alicyclic hydrocarbongroup includes a saturated alicyclic hydrocarbon group (e.g., acycloalkyl group and the like) such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like; an unsaturatedalicyclic hydrocarbon group (e.g., cycloalkenyl group, cycloalkadienylgroup and the like) such as 1-cyclopentenyl, 2-cyclopentenyl,3-cyclpentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyland the like.

As the alicyclic-aliphatic hydrocarbon group, an alicyclic hydrocarbongroup listed above attached to an aliphatic hydrocarbon group listedabove (e.g., a cycloalkyl-alkyl group, a cycloalkenyl-alkyl group andthe like) are exemplified, and an alicyclic-aliphatic hydrocarbon grouphaving 4 to 9 carbon atom is preferred. Such alicyclic-aliphatichydrocarbon group includes cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl,3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl,3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl,cycloheptylmethyl, cycloheptylethyl, and the like.

As the aromatic-aliphatic hydrocarbon group, an aromatic-aliphatichydrocarbon group having 7 to 13 carbon atoms (e.g., an aralkyl group,an arylalkenyl group and the like) is preferred. Such araliphatichydrocarbon group includes a phenylalkyl having 7 to 9 carbon atoms suchas benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl and the like; a naphthylalkyl having 11 to 13 carbonatoms such as α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl,β-naphthylethyl and the like; a phenylalkenyl having 8 to 10 carbonatoms such as styryl and the like; a naphthylalkenyl having 12 to 13carbon atoms such as 2-(2-naphthylvinyl) and the like.

As the aromatic hydrocarbon group, an aromatic hydrocarbon group having6 to 14 carbon atoms (e.g., an aryl group and the like) is preferred.Such aromatic hydrocarbon group includes phenyl, naphthyl, anthryl,phenanthryl, acenaphthylenyl, biphenylyl and the like, and, among these,those preferred are phenyl, 1-naphthyl, 2-naphthyl and the like.

(1-2) Definition of Heterocyclic Group for R¹

A heterocyclic group in “an optionally substituted heterocyclic group”represented by R¹ in Formulae (I-1) and (II) includes a 5- to 7-memberedmonocyclic or condensed heterocyclic group having as its constituentatoms 1 to 4 hetero atoms selected from the group consisting of anoxygen atom, a sulfur atom and a nitrogen atom in addition to carbonatoms. As the condensed heterocyclic ring, a 5- to 7-membered monocyclicheterocyclic ring condensed with a 6-membered ring containing 1 to 2nitrogen atoms, with a benzene group, or with a 5-membered ringcontaining one sulfur atom may be exemplified.

Examples of the heterocyclic group are an aromatic heterocyclic groupsuch as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl,1,3,4-oxadiazol-2-yl, 1,3,4-thiaziazol-2-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-quinolyl,3-quinolyl, 4-quinolyl, 2-quinazolyl, 4-quinazolyl, 2-quinoxalyl,2-benzoxazolyl, 2-benzothiazolyl, benzimidazol-1-yl, benzimidazol-2-yl,indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyridin-6-yl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and thelike as well as a non-aromatic heterocyclic group such as1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl,1-hexamethyleneiminyl, oxazolidin-3-yl, thiazolidin-3-yl,imidazolidin-3-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl,2,4-dioxooxazolidin-3-yl, 2,4-dioxothiazolidin-3-yl and the like.

A heterocyclic group is preferably pyridyl, oxazolyl, thiazolyl,benzoxazolyl or benzothiazolyl.

(1-3) Definition of Substituents of Hydrocarbon and/or HeterocyclicGroup for R¹

Each of the hydrocarbon group and the heterocyclic group represented byR¹ in Formulae (I-1) and (II) optionally have 1 to 5, preferably 1 to 3substituents on its possible positions. Such substituents include anoptionally substituted aliphatic hydrocarbon group, an optionallysubstituted alicyclic hydrocarbon group, an optionally substitutedaromatic hydrocarbon group, an optionally substituted aromaticheterocyclic group, an optionally substituted non-aromatic heterocyclicgroup, a halogen atom, a nitro group, an optionally substituted aminogroup, an optionally substituted acyl group, an optionally substitutedhydroxy group, an optionally substituted thiol group, an optionallyesterified or amide-derivatized carboxyl group. The substituentsrepresented by “optionally substituted” are a C₁₋₆ alkyl group, a C₁₋₆alkoxy group, a halogen (e.g., fluorine, chlorine, bromine, iodine andthe like), nitro group, a C₁₋₆ halo-alkyl group, a C₁₋₆ halo-alkoxygroup.

Examples of the aliphatic hydrocarbon group are a straight or branchedaliphatic hydrocarbon group having 1 to 15 carbon atoms, such as analkyl group, an alkenyl group, an alkynyl group and the like.

A preferred alkyl group includes an alkyl group having 1 to 10 carbonatoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.

A preferred alkenyl group includes an alkenyl group having 2 to 10carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl,1-octenyl and the like.

A preferred alkynyl group includes ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,1-heptynyl, 1-octynyl and the like.

As the alicyclic hydrocarbon group, a saturated or unsaturated alicyclichydrocarbon group having 3 to 12 carbon atoms, such as a cycloalkylgroup, a cycloalkenyl group, a cycloalkadienyl group, may beexemplified.

Preferred examples of the cycloalkyl group are a cycloalkyl group having3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.1.1]nonyl,bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like.

Preferred examples of the cycloalkenyl group are a cycloalkenyl grouphaving 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl,3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.

Preferred examples of the cycloalkanedienyl group are acycloalkanedienyl group having 4 to 10 carbon atoms, such as2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yland the like.

Preferred examples of the aromatic heterocyclic group are a 5- to7-membered aromatic monocyclic group having as its constituent atoms 1to 4 hetero atoms selected from the group consisting of an oxygen atom,a sulfur atom and a nitrogen atom in addition to carbon atoms, such asfuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like; abicyclic or tricyclic aromatic condensed heterocyclic ring having as itsconstituent atoms 1 to 5 hetero atoms selected from the group consistingof an oxygen atom, a sulfur atom and a nitrogen atom in addition tocarbon atoms, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl,indolyl, isoindolyl, 1H -indazolyl, benzimidazolyl, benzooxazolyl,benzothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl,quinazolyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl,pteridinyl, carbazolyl, α-carbonylyl, β-carbonylyl, γ-carbonylyl,acridinyl, phenoxadinyl, phenothiazinyl, phenazinyl, phenoxathiinyl,thianthrenyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl and thelike.

Preferred examples of the non-aromatic heterocyclic group are oxiranyl,azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl,pyrrolidinyl, piperidinyl, morpholino, thiomorpholino and the like.

Examples of the halogen atom are fluorine, chlorine, bromine and iodine,with fluorine and chlorine being preferred.

An optionally substituted amino group is an amino group optionally mono-or di-substituted with, for example, an alkyl group having 1 to 10carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenylgroup having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10carbon atoms, an acyl group having 3 to 10 carbon atoms (e.g., analkanoyl group having 2 to 10 carbon atoms, an arylcarbonyl group having7 to 13 carbon atoms and the like), or an aryl group having 6 to 12carbon atoms. The acyl group has the same definition mentioned below forthe acyl group in an optionally substituted acyl group.

The substituted amino group includes methylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino, diallylamino,cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino,N-methyl-N-phenylamino and the like.

The acyl group in an optionally substituted acyl group is an acyl grouphaving 1 to 13 carbon atoms, such as formyl, as well as a carbonyl groupbound to an alkyl group having 1 to 10 carbon atoms, a cycloalkyl grouphaving 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbonatoms, a cycloalkenyl group having 3 to 10 carbon atoms, an aryl grouphaving 6 to 12 carbon atoms and an aromatic heterocyclic group (e.g.,thienyl, furyl, pyridyl and the like).

Preferred examples of the acyl group are acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,oxtanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, isonicotinoyl and the like.

Such acyl group optionally has one to three substituents on its possiblepositions, and such substituents include an alkyl group having 1 to 3carbon atoms, an alkoxy group having 1 to 3 carbon atoms, halogen (e.g.,fluorine, chlorine, iodine and the like), nitro, hydroxy, amino and thelike.

Other types of acyl group are represented by a group of the formula:—COR¹¹, —SO₂R¹⁴, —SOR¹⁵ or —PO₃R¹⁶R¹⁷ wherein R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷are independently an optionally substituted hydrocarbon group.

Examples of the “optionally substituted hydrocarbon group” representedby R¹¹, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are an alkyl group having 1 to 10 carbonatoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl grouphaving 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbonatoms, an aryl group having 6 to 12 carbon atoms.

The optionally substituted hydroxy group includes a hydroxy group, analkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxygroup, an aryloxy group and the like, each of which may optionally besubstituted.

Preferred examples of the alkoxy group are an alkoxy group having 1 to10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy,cyclohexyloxy and the like.

Preferred examples of the alkenyloxy group are an alkenyloxy grouphaving 2 to 10 carbon atoms, such as allyloxy, crotyloxy, 2-pentenyloxy,3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy and thelike.

Preferred examples of the aralkyloxy group are an aralkyloxy grouphaving 7 to 10 carbon atoms such as phenyl-C₁₋₄ alkyloxy (e.g.,benzyloxy, phenethyloxy and the like) and the like.

Preferred examples of the acyloxy group are an acyloxy group having 2 to13 carbon atoms, preferably an alkanoyloxy having 2 to 4 carbon atoms(e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and the like)and the like.

Preferred examples of the aryloxy group are an aryloxy group having 6 to14 carbon atoms such as phenoxy, naphthyloxy and the like.

Each of an alkoxy group, an alkenyloxy group, an aralkyloxy group, anacyloxy group and an aryloxy group described above may have 1 to 2substituents on its possible positions, and such substituents include ahalogen (e.g., fluorine, chlorine, bromine and the like), an alkoxygroup having 1 to 3 carbon atoms. For example, a substituted aryloxygroup may be 4-chlorophenoxy, 2-methoxyphenoxy and the like.

The optionally substituted thiol group includes a thiol, an alkylthio, acycloalkylthio, an aralkylthio, an acylthio, an arylthio, aheteroarylthio and the like.

Preferred examples of the alkylthio group are an alkylthio group having1 to 19 carbon atoms such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio,pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio,nonylthio and the like.

Preferred examples of the cycloalkylthio group are a cycloalkylthiogroup having 3 to 10 carbon atoms such as cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

Preferred examples of the aralkylthio group are an aralkylthio grouphaving 7 to 10 carbon atoms such as phenyl-C₁₋₄ alkylthio (e.g.,benzylthio, phenethylthio and the like) and the like.

Preferred examples of the acylthio group are an acylthio group having 2to 13 carbon atoms, preferably an alkanoylthio group having 2 to 4carbon atoms (e.g., acetylthio, propionylthio, butyrylthio,isobutyrylthio and the like) and the like.

Preferred examples of the arylthio group are an arylthio group having 6to 14 carbon atoms, such as phenylthio, naphthylthio and the like.

Preferred examples of the heteroarylthio group are 2-pyridylthio,3-pyridylthio as well as 2-imidazolylthio, 1,2,4-triazol-5-ylthio andthe like.

The optionally esterified carboxyl group includes a carboxyl group, analkoxycarbonyl group having 2 to 5 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), anaralkyloxycarbonyl group having 8 to 10 carbon atoms (e.g.,benzyolxycarbonyl and the like), an aryloxycarbonyl group having 7 to 15carbon atoms optionally substituted with one or two alkyl groups having1 to 3 carbon atoms (e.g., phenoxycarbonyl, p-tolyloxycarbonyl and thelike) and the like.

The optionally substituted amide-derived carboxyl group includes a grouprepresented by Formula: —CON(R¹²)(R¹³) wherein R¹² and R¹³ may be sameor different and is hydrogen, an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group.

The hydrocarbon group and the heterocyclic group in “an optionallysubstituted hydrocarbon group” and “an optionally substitutedheterocyclic group” represented by R¹² and R¹³ includes an aliphatichydrocarbon group, an alicyclic hydrocarbon group and an aromatic andheterocyclic group exemplified as the same described in the above (1-1)and (1-2), respectively. Such hydrocarbon groups optionally have 1 to 3substituents on its possible positions, and such substituents include ahalogen (e.g., fluorine, chlorine, bromine, iodine and the like), analkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4carbon atoms and the like.

A substituent in the hydrocarbon group and the heterocyclic grouprepresented by R¹ in Formulae (I-1) and (II) is preferably an alkylgroup having 1 to 10 carbon atoms, a cycloalkyl group having 1 to 10carbon atoms, an aromatic heterocyclic group, an aryl group having 6 to14 carbon atoms, more preferably an alkyl group having 1 to 3 carbonatoms, a cycloalkyl group having 3 to 7 carbon atoms, furyl, thienyl,phenyl and naphthyl.

The substituent in the hydrocarbon group and the heterocyclic grouprepresented by R¹, when it is an alicyclic hydrocarbon group, anaromatic hydrocarbon group, an aromatic heterocyclic group or anon-aromatic heterocyclic group, optionally have one or more, preferably1 to 3 appropriate substituents, and such substituents include an alkylgroup having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbonatoms, a cycloalkyl group having 3 to 10 carbon atoms, an aryl grouphaving 6 to 14 carbon atoms (e.g., phenyl, naphthyl and the like), anaromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl,thiazolyl and the like), a non-aromatic heterocyclic group (e.g.,tetrahydrofuryl, morpholino, thiomorpholino, piperidino, pyrrolidinyl,piperazinyl and the like), an aralkyl group having 7 to 9 carbon atoms,amino group, an amino group mono- or di-substituted with an alkyl grouphaving 1 to 4 carbon atoms or with an acyl group having 2 to 8 carbonatoms (e.g., an alkanoyl group and the like), an amidino group, an acylgroup having 2 to 8 carbon atoms (e.g., alkanoyl group and the like),carbamoyl group, a carbamoyl group mono- or di-substituted with an alkylgroup having 1 to 4 carbon atoms, sulfamoyl group, a sulfamoyl groupmono- or di-substituted with an alkyl group having 1 to 4 carbon atoms,carboxyl group, an alkoxycarbonyl group having 2 to 8 carbon atoms,hydroxy group, an alkoxy group having 1 to 6 carbon atoms, an alkenyloxygroup having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms, an aryloxygroup having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy and thelike), thiol group, an alkylthio group having 1 to 6 carbon atoms, anaralkylthio group having 7 to 9 carbon atoms, an arylthio group having 6to 14 carbon atoms (e.g., phenylthio, naphthylthio and the like),sulfonyl group, cyano group, azide group, nitro group, nitroso group, ahalogen atom (e.g., fluorine chlorine, bromine, iodine) and the like.

(1-4) Preferred Examples of R¹

R¹ in Formulae (I-I) and (II) is preferably an optionally substitutedheterocyclic group, and more preferably pyridyl, oxazolyl, thiazolyl ortriazolyl each of which is optionally substituted. A particularlypreferable R¹ is pyridyl, oxazolyl, thiazolyl or triazolyl whichoptionally have 1 to 2 substituents selected from the group consistingof an alkyl having 1 to 3 carbon atoms a cycloalkyl having 3 to 7 carbonatoms, furyl, thienyl, phenyl and naphthyl. The furyl, thienyl, phenyland naphthyl optionally have substituents selected from an alkyl having1 to 3 carbon atoms, an alkoxy having 1 to 3 carbon atoms, a halogen(e.g., fluorine, chlorine, bromine, iodine and the like) and halo-alkylhaving 1 to 3 carbon atoms.

Such preferred ring of an optionally substituted heterocyclic group oran optionally substituted cyclic hydrocarbon group of R¹ is selectedfrom the group represented by formulae of

The ring optionally has one or two substituents which is selected fromthe group of a phenyl, a furyl, a thienyl and a C₁₋₄ alkyl. The group ofa phenyl, a furyl and a thienyl optionally have substituents selectedfrom C₁₋₆ alkyl group, C₁₋₆ alkoxy group, a halogen (e.g., fluorine,chlorine, bromine, iodine and the like), nitro group, C₁₋₆ halo-alkylgroup, C₁₋₆ halo-alkoxy group.

Further preferred one for R¹ is a formula of

wherein Ph is an optionally substituted phenyl group, and R″ is ahydrogen or an optionally substituted C₁₋₆ alkyl group.

The substituents of Ph and the C₁₋₆ alkyl group of R″ are a C₁₋₆ alkoxygroup, a halogen (e.g., fluorine, chlorine, bromine, iodine and thelike), a nitro group, a C₁₋₆ halo-alkyl group or a C₁₋₆ halo-alkoxygroup.

(2) Definition of X

In Formulae (I-1), (I-2) and (II) X is a bond, —CO—, —CH(OH)— or a grouprepresented by —NR⁶— wherein R⁶ hydrogen, is an optionally substitutedalkyl group, with a bond, —CH(OH)— or —NR⁶— being preferred and a bondor —NR⁶— being more preferred.

An alkyl group in “an optionally substituted alkyl group” represented byR⁶ includes an alkyl group having 1 to 4 carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl and thelike. Such alkyl group optionally have 1 to 3 substituents on itspossible positions, and such substituents include a halogen (fluorine,chlorine, bromine, iodine), an alkoxy group having 1 to 4 carbon atoms(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, t-butoxy and the like), hydroxy group, nitro group, an acylgroup having 1 to 4 carbon atoms (e.g., an alkanoyl group having 1 to 4carbon atoms such as formyl, acetyl, propionyl and the like).

(3) Definition of n & Y

In Formulae (I-1), (I-2) and (II), n is an integer of 1 to 3, preferably1 to 2.

In Formulae (I-1), (I-2) and (II), Y is —O—, —S—, —SO—, —SO₂— or —NR⁷—wherein R⁷ is an hydrogen optionally substituted alkyl group, with —O—,—S— or —NR⁷— being preferred. “An optionally substituted alkyl group”represented by R⁷ includes those exemplified as “an optionallysubstituted alkyl group” represented by R⁶ described above.

(4) Definition of Ring A

Ring A in Formulae (I-1), (I-2) and (II) represents a benzene ring, andoptionally has additional 1 to 3 substituents on its possible positions.Such substituents include an alkyl group, an optionally substitutedhydroxy group, a halogen atom, an optionally substituted acyl group,nitro group, and an optionally substituted amino group, each of which isexemplified as a substituent on a hydrocarbon group and a heterocyclicgroup represented by R¹.

Such substituent is preferably an alkyl group having 1 to 4 carbonatoms, an alkoxy group having 1 to 4 carbon atoms or a halogen atom. Thering A is preferably a non-substituted benzene ring.

In Formulae (I-1), and (II), a moiety:

(5) Definition of P

In Formulae (I-1), (I-2) and (II), p is an integer of 1 to 8, preferablyan integer of 1 to 3.

(6) Definition of R²

In Formulae (I-1), (I-2) and (II), “an optionally substitutedhydrocarbon group” represented by R² may be one exemplified as “anoptionally substituted hydrocarbon group” represented by R¹.

“An optionally substituted heterocyclic group” represented by R² may beone exemplified as “an optionally substituted heterocyclic group”represented by R¹.

In Formulae (I-1), (I-2) and (II), R² is preferably an optionallysubstituted hydrocarbon group. More preferably, R² is an aliphatichydrocarbon group, an alicyclic hydrocarbon group, an aromatic-aliphatichydrocarbon group or an aromatic hydrocarbon group each of which isoptionally substituted, and particularly preferred is an alkyl grouphaving 1 to 4 carbon atoms, a phenylalkyl group having 8 to 10 carbonatoms, an aryl group having 6 to 14 carbon atoms, each of which isoptionally substituted.

A substituent which is optionally present on each of the hydrocarbongroups described above is preferably a halogen atom, an alkoxy grouphaving 1 to 4 carbon atoms, an aryloxy group having 6 to 14 carbon atomsand an aromatic heterocyclic group (e.g., furyl, thienyl).

(7) Definition of q, and m

In Formulae (I-1) and (I-2), q is an integer of 0 to 6, preferably 0 to4. m is 0 or 1. In Formulae (I-1) where R¹ is ethoxymethyl, a C₁₋₃alkyl, phenyl or p-methoxyphenyl, q is an integer of 1 to 6.

In Formulae (II), q is an integer of 0 to 6, preferably 0 to 4. m is 0or 1.

(8) Definition of R³

R³ is a hydroxy group, OR⁸ (R⁸ is an optionally substituted hydrocarbongroup.) or NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group or R⁹ and R¹⁰ combine together to form a ring).

In Formulae (I-1), (I-2) and (II), “an optionally substitutedhydrocarbon group” represented by R⁸ includes one exemplified as “anoptionally substituted hydrocarbon group” represented by R¹. Aparticularly preferred R³ is hydroxy group.

In Formulae (I-1), (I-2) and (II), “an optionally substitutedhydrocarbon group” represented by R⁹ and R¹⁰ includes one exemplified as“an optionally substituted hydrocarbon group” represented by R¹.

In Formulae (I-1), (I-2) and (II), “an optionally substitutedheterocyclic group” represented by R⁹ and R¹⁰ includes one exemplifiedas “an optionally substituted heterocyclic group” represented by R¹.

In Formulae (I-1), (I-2) and (II), “an optionally substituted acylgroup” represented by R⁹ and R¹⁰ includes one exemplified as “anoptionally substituted acyl group” represented by R¹.

In Formulae (I-1), (I-2) and (II), R⁹ and R¹⁰ optionally combinetogether to form a ring such as 1-pyrrolidinyl, 1-piperidinyl,1-hexamethyleneiminyl, 4-morpholino, 4-thiomorpholino.

(9) Definition of R⁴ & R⁵

“An optionally substituted alkyl group” represented by R⁴ and R⁵ inFormulae (I-1), and (II) includes the same as “an optionally substitutedalkyl group” represented by R⁶ described above.

“An optionally substituted hydrocarbon group” and “an optionallysubstituted heterocyclic group” represented by R⁹ and R¹⁰ in Formulae(I-1), (I-2) and (II) includes the same as “an optionally substitutedhydrocarbon group” and “an optionally substituted heterocyclic group”represented by R¹² and R¹³, respectively, described above.

“An optionally substituted hydrocarbon group” represented by R¹¹ inFormulae (I-1), (I-2) and (II) includes an alkyl group having 1 to 4carbon atoms, an aryl group having 6 to 10 carbon atoms optionallysubstituted with an alkyl group having 1 to 4 carbon atoms or with ahalogen atom. Such alkyl group having 1 to 4 carbon atoms in “an alkylgroup having 1 to 4 carbon atoms” and “an aryl group having 6 to 10carbon atoms optionally substituted with an alkyl group having 1 to 4carbon atoms or with a halogen atom” represented by R⁸ includes methyl,ethyl, propyl, butyl, isobutyl, sec-butyl, t-butyl and the like, withmethyl and ethyl being preferred. A halogen in “an aryl group having 6to 10 carbon atoms optionally substituted with an alkyl group having 1to 4 carbon atoms or with a halogen atom” includes fluorine, chlorine,bromine, iodine and the like, with chlorine being preferred, and an arylgroup having 6 to 10 carbon atoms may include phenyl and naphthyl, withphenyl being preferred.

(10) E-form and/or Z-form Compound

A compound represented by Formulae (I-1), (I-2) and (II) is present inE- and Z-isomers with regard to the imino bond. Said compound may beeither single one of E- or Z-form, or may be the mixture of the two.

O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime of methyl pyruvateand [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminoxy propionicacid are known compounds disclosed in WO96/02507, and excluded fromFormula (I-1).

(11) Preferred Embodiments

Among the compounds of Formula (I-1), one of the preferred embodimentsof the present invention is a compound represented by the formula of

wherein R′ is a phenyl, furyl or thienyl which optionally hassubstituents selected from a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, ahalogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitrogroup, a C₁₋₆ halo-alkyl group, a C₁₋₆ halo-alkoxy group; R″ is ahydrogen or an optionally substituted C₁₋₆ alkyl (more preferably ahydrogen, methyl or ethyl); R²′ is a phenyl which is optionallysubstituted by at least one substituent selected from a group of ahydrogen, a C₁₋₆ alkyl, a C₁₋₆ alkoxy and a halogen; q is an integer of1 to 6; and R^(3′) is a hydroxy, a C₁₋₆ alkoxy or —NR⁹R¹⁰ in which R⁹and R¹⁰ are independently selected from the group of a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group or an optionally substituted acyl group, or R⁹ andR¹⁰ combine together to form a ring; a ring A is an optionallysubstituted benzene ring; or a salt thereof.

Another preferred embodiment of the present invention is a compoundrepresented by a formula of

wherein each symbol has the same definition mentioned above; or a saltthereof.

Preferred specific examples of the compound represented by Formulae(I-1), (I-2) and (II) are Compound (1) to (10) listed below.

(1)Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-phenylaceticacid

(2)Z-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid

(3)Z-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid

(4)Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)aceticacid

(5)Z-4-(4-fluorophenyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid

(6)Z-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid

(7)E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid

(8)E-4-(4-fluorophenyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid

(9)E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyamide

(10)E-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoicacid

These compounds may hereinafter be abbreviated as Compound (1), Compound(2) or the like.

(12) Examples of Salts

A salt of a compound represented by Formula (I-1), (I-2) or (II) (whichmay hereinafter be abbreviated as Compound (I-1), (I-2) or (II)) ispreferably a pharmacologically acceptable salt, such as a salt with aninorganic base, a salt with an organic base, a salt with an inorganicacid, a salt with an organic salt, a salt with a basic or acidic aminoacid and the like.

Preferred examples of the salt with an inorganic base are an alkalimetal salt such as a sodium salt and a potassium salt; an alkaline earthmetal salt such as a magnesium salt; as well as an aluminum salt and anammonium salt and the like.

Preferred examples of the salt with an organic base are salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferred examples of the salt with an inorganic acid are salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferred examples of the salt with an organic acid are salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferred examples of the salt with a basic amino acid are salts witharginine, lysine, ornithine and the like, while preferred examples of asalt with an acidic amino acid are salts with aspartic acid, glutamicacid and the like.

Among the salts described above, those preferred are sodium salts,potassium salts, hydrochlorides and the like.

(13) Formulation

A compound represented by Formula (I-1), (I-2) or (II) and a saltthereof (which may hereinafter be abbreviated as a compound according tothe present invention) has a low toxicity, and can be formulatedtogether with a pharmacologically acceptable carrier into apharmaceutical composition, which may be used as an agent for preventionand/or treatment of various diseases discussed below in mammals (e.g.,human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, monkey andthe like).

The pharmacologically acceptable carrier employed here is selected fromvarious customary organic or inorganic materials used as materials forpharmaceutical formulations, and may be incorporated as excipients,glidants, binders and disintegrants in a solid formulation; vehicles,solubilizers, suspending agents, tonicity agents, buffer, analgesicagents in a liquid formulation. If necessary, pharmaceutical additivessuch as preservatives, antioxidants, colorants, sweeteners may also beadded.

Preferred examples of the excipients are lactose, sugar, D-mannitol,D-sorbitol, starch, α-starch, dextrin, crystalline cellulose,low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose,gum arabic, pullulan, light silicic anhydride, synthetic aluminumsilicate, magnesium aluminate metasilicate and the like.

Preferred examples of the glidants are magnesium stearate, calciumstearate, talc, colloidal silica and the like.

Preferred examples of the binders are α-starch, sucrose, gelatin, gumarabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sugar, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

Preferred examples of the disintegrants are sugar, starch,carboxymethylcellulose, potassium carboxymethylcellulose, croscarmellosesodium, sodium carboxymethyl starch, light silicic anhydride,low-substituted hydroxypropylcellulose and the like.

Preferred examples of the vehicles are water for injection,physiological saline, Ringer's solution, alcohols, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil, cotton seed oiland the like.

Preferred examples of the solubilizers are polyethylene glycol,propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate, sodium salicylate, sodium acetate and the like.

Preferred examples of the suspending agents are a surfactant such asstearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate and the like; a hydrophilic polymer such aspolyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and polysorbates, polyoxyethylenehydrogenated castor oil and the like.

Preferred examples of the tonicity agents are sodium chloride, glycerin,D-mannitol, D-sorbitol, glucose and the like.

Preferred examples of the buffer solution are the solutions ofphosphates, acetates, carbonates, citrates and the like.

Preferred examples of the analgesic agents includes benzylalcohol andthe like.

Preferred examples of the preservatives are p-oxybenzoates,chlorobutanol, benzylalcohol, phenethylalcohol, dehydroacetic acid,sorbic acid and the like.

Preferred examples of the antioxidants are sulfites, ascorbates and thelike.

Preferred examples of the colorants are a water soluble tar pigments(e.g., edible pigments such as edible color Red No.2 and No.3, ediblecolor Yellow No.4 and No.5, edible color Blue No.1 and No.2), awater-insoluble lake pigments (e.g., aluminum salts of the water solubleedible tar pigments listed above and the like), a natural pigment (e.g.,β-carotene, chlorophyll, iron oxide red and the like) and the like.

Preferred examples of the sweeteners are saccharin sodium, potassiumglycyrrhizinate, Aspartame, steviocides and the like.

(14) Dosage Form

A dosage form of a pharmaceutical composition includes an oralformulation such as a capsule (including a soft capsule and amicrocapsule), a granule, a powder, a syrup, an emulsion, a suspensionand the like; a non-oral formulation such as a formulation for injection(e.g., subcutaneous injection formulation, intravenous injectionformulation, intramuscular injection formulation, intraperitonealinjection formulation and the like), a formulation for drip infusion, aformulation for external application (e.g., nasal formulation,percutaneous formulation, ointments and the like), a suppository (e.g.,rectal suppository, vaginal suppository and the like), a pellet, aformulation for drip infusion and the like, all of which can safely begiven via an oral or a non-oral route.

The pharmaceutical composition may be produced by a conventional methodin the field of pharmaceutical technology, for example, a methoddescribed in Japanese Pharmacopoeia. A method for producing aformulation is described in detail below.

An oral formulation is, for example, prepared by admixing an activeingredient with an excipient (e.g., lactose, sugar, starch, D-mannitoland the like), a disintegrant (e.g., calcium carboxymethylcellulose andthe like), a binder (e.g., α starch, gum arabic, carboxymethylcellulose,hydroxypropyl cellulose, polyvinylpyrrolidone and the like), or aglidant (e.g., talc, magnesium stearate, polyethylene glycol 6000 andthe like), followed by compaction molding, further followed, ifnecessary, by coating with a coating base by a known method for thepurpose of masking a taste, obtaining an enteric dissolution or asustained release.

Such coating base includes a sugar coating base, a water soluble filmcoating base, an enteric coating base, a sustained release film coatingbase and the like.

A sugar coating base includes a sugar, which may be used in combinationwith one or more materials selected from the group consisting of talc,sedimentation calcium carbonate, gelatin, gum arabic, pullulan, carnaubawax and the like.

A water soluble film coating base includes a cellulose-based polymersuch as hydroxpropylcellulose, hydroxypropylmethylcellulose,methylhydroxyethylcellulose and the like; a synthetic polymer such aspolyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer E[Eudragit E (trade name), Rohm Pharma], polyvinylpyrrolidone and thelike; and a polysaccharide such as pullulan.

An enteric film coating base includes a cellulose-based polymer such ashydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, carboxymethylethylcellulose, cellulose acetatephthalate and the like; an acrylic acid-based polymer such asmethacrylic acid copolymer L [Eudragit L (trade name), Röhm Pharma],methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), RöhmPharma], methacrylic acid copolymer S [Eudragit S (trade name), RöhmPharma] and the like; a naturally-occurring material such as shellac.

A sustained release film coating base includes a cellulose-based polymersuch as ethylcellulose; an acrylic acid-based polymer such asaminoalkylmethacrylate copolymer RS [Eudragit RS (trade name), RöhmPharma], ethylacrylatemethylmethacrylate copolymer suspension [EudragitNE (trade name), Röhm Pharma] and the like.

A mixture of two or more coating bases described above may also beemployed in a certain appropriate ratio. A light-shielding material suchas titanium oxide and iron dioxide or trioxide may also be employed inthe coating.

An injection formulation may be prepared by dissolving, suspending oremulsifying an an active ingredient together with a dispersant (e.g.,polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and thelike), polyethylene glycol, carboxymethylcellulose, sodium alginate andthe like, a preservative (e.g., methylparaben, propylparaben,benzylalcohol, chlorobutanol, phenol and the like), a tonicity agent(e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose andthe like) and the like, in an aqueous solvent (e.g., distilled water,physiological saline, Ringer's solution and the like) or a lipophilicsolvent (e.g., a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil and the like or propylene glycol). In this procedure,an additive such as a solubilizer (e.g. sodium salicylate, sodiumacetate and the like), a stabilizer (e.g., human serum albumin and thelike), an analgesic agent (e.g., benzylalcohol and the like) may also beemployed if necessary.

(15) Composition

The other aspect of the present invention is a pharmaceuticalcomposition comprising a compound represented by Formula (II)

wherein R¹ is an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; X is a bond, —CO—, —CH(OH)—or a group represented by —NR⁶— wherein R⁶ is a hydrogen atom or anoptionally substituted alkyl group; n is an integer of 1 to 3; Y is anoxygen atom, a sulfur atom, —SO—, —SO₂— or a group represented by —NR⁷—wherein R⁷ is a hydrogen atom or an optionally substituted alkyl group;ring A is a benzene ring optionally having additional one to threesubstituents; p is an integer of 1 to 8; R² is a hydrogen atom, anoptionally substituted hydrocarbon group or an optionally substitutedheterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R³ is ahydroxy group, OR⁸ (R⁸ is an optionally substituted hydrocarbon group.)or NR⁹R¹⁰ (R⁹ and R¹⁰ are the same or different groups which areselected from a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group or an optionallysubstituted acyl group or R⁹ and R¹⁰ combine together to form a ring);R⁴ and R⁵ are the same or different groups which are selected from ahydrogen atom or an optionally substituted hydrocarbon group wherein R⁴may form a ring with R²; or a salt thereof. Each above-mentionedsubstituent has the same detailed definition of the corresponding onedefined for Formula (I-1).

Especially, the pharmaceutical composition can be used for prevention ortreatment of diseases such as diabetes mellitus, hyperlipemia, impairedglucose tolerance, an inflammatory disease, an arteriosclerosis and thelike.

Among these compositions, a preferred one is a composition a compoundrepresented by a formula of

wherein R′ is a phenyl, furyl or thienyl which optionally hassubstituents selected from a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, ahalogen (e.g., fluorine, chlorine, bromine, iodine and the like), nitrogroup, a C₁₋₆ halo-alkyl group, a C₁₋₆ halo-alkoxy group; R″ is ahydrogen or a C₁₋₆ alkyl (more preferably, a hydrogen, methyl or ethyl); R^(2′) is a phenyl which is optionally substituted by at least oneselected from a group of a hydrogen, a C₁₋₆ alkyl, a C₁₋₆ alkoxy and ahalogen; q is an integer of 1 to 6; and R^(3′) is a hydroxy, an alkoxyor —NR⁹R¹⁰ in which R⁹ and R¹⁰ are independently selected from the groupof a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group or an optionally substitutedacyl group, or R⁹ and R¹⁰ combine together to form a ring; a ring A isan optionally substituted benzene ring; or a salt thereof.

Another preferred composition of the present invention is a compositioncomprising a compound represented by a formula of

wherein each symbol has the same definition mentioned above; or a saltthereof.

(16) Agent

According to the useful function of the compound of the presentinvention, the compound can be used as an insulin sensitivity enhancingagent; an insulin resistance improving agent; an agent for controllingor adjusting retinoid-related receptor; a ligand of a peroxisomeproliferator-activated receptors; a retinoid X receptor ligand; etc.

A compound according to the present invention has a blood sugar reducingeffect, a blood lipid reducing effect, a blood insulin reducing effect,an insulin sensitivity enhancing effect, an insulin resistance improvingeffect and retinoid-related receptor function adjuster activities. Aretinoid-related receptor used here is encompassed in nuclear receptors,and is a DNA-binding transcription factor having as a function adjustera signal molecule such as an oil-soluble vitamin, and may be any of amonomer receptor, a homodimer receptor and a heterodimer receptor.

A monomer receptor is exemplified by retinoid O receptor (hereinafterabbreviated occasionally as ROR) α (GenBank Accession No.L14611), RORβ(GenBank Accession No.L14160), RORγ (GenBank Accession No.U16997);Rev-erbα (GenBank Accession No.M24898), Rev-erbβ (GenBank AccessionNo.L31785); ERRα (GenBank Accession No.X51416), ERRβ (GenBank AccessionNo.X51417); Ftz-FIα (GenBank Accession No.S65876), Ftz-FIβ (GenBankAccession No.M81385); TIx (GenBank Accession No.S77482); GCNF (GenBankAccession No.U14666) and the like.

A homodimer receptor may for example be a homodimer formed from retinoidX receptor (hereinafter abbreviated occasionally as RXR) α (GenBankAccession No.X52773), RXRβ (GenBank Accession No.M84820), RXRγ (GenBankAccession No.U38480); COUPα (GenBank Accession No.X12795), COUPβ(GenBank Accession No.M64497), COUPγ (GenBank Accession No.X12794); TR2α(GenBank Accession No.M29960), TR2β (GenBank Accession No.L27586); or,HNF4α (GenBank Accession No.X76930), HNF4γ (GenBank Accession No.Z49826)and the like.

A heterodimer receptor may for example be a heterodimer formed fromretinoid receptor X (RXRα, RXRβ or RXRγ) described above together withone receptor selected from the group consisting of retinoid A receptor(hereinafter abbreviated occasionally as RAR) α (GenBank AccessionNo.X06614), RARβ (GenBank Accession No.Y00291), RARγ (GenBank AccessionNo.M24857); a thyroidal hormone receptor (hereinafter abbreviatedoccasionally as TR) α (GenBank Accession No.M24748), TRβ (GenBankAccession No.M26747); a vitamin D receptor (VDR) (GenBank AccessionNo.J03258); a peroxisome proliferator-activated receptor (hereinafterabbreviated occasionally as PPAR) α (GenBank Accession No.L02932), PPARβ(PPAR δ) (GenBank Accession No.U10375), PPARγ (GenBank AccessionNo.L40904); IXRα (GenBank Accession No.U22662), LXRβ (GenBank AccessionNo.U14534); FXR (GenBank Accession No.U18374); MB67 (GenBank AccessionNo.L29263); ONR (GenBank Accession No.X75163; and NURα (GenBankAccession No.L13740), NURβ (GenBank Accession No.X75918), NURγ (GenBankAccession No.U12767).

Compound (I-2) and its salts exhibit excellent function adjusteractivity especially toward retinoid X receptors (RXRα, RXRβ, RXRγ) andperoxisome proliferator-activated receptors (PPARα, PPARβ ((PPAR δ),PPARγ) among those retinoid-related receptors listed above.

In addition Compound (II) or its salts exhibit excellent ligand activitytoward a heterodimer receptor formed from a retinoid X receptor and aperoxisome proliferator-activated receptor, preferably a peroxisomeproliferator-activate receptor as in the heterodimer receptor formedfrom RXRα and PPARγ.

Accordingly, a retinoid-related receptor function adjuster according tothe present invention is used advantageously as a peroxisomeproliferator-activate receptor ligand or a retinoid X receptor ligand.

(17) Diseases to be Treated

Accordingly, a compound or a pharmaceutical composition according to thepresent invention can be used for the prevention or treatment ofdiabetes mellitus (e.g., insulin-dependent diabetes mellitus(type-1diabetes mellitus), non-insulin-dependent diabetes mellitus(type-2diabetes mellitus), pregnancy diabetes mellitus and the like),hyperlipemia (e.g., hypertriglycemia, hypercholesterolemia, hypoHDLemiaand the like), insulin insensitivity, insulin resistance, and impairedglucose tolerance (IGT).

A compound or a pharmaceutical composition according to the presentinvention may also be used for the prevention or treatment of diabeticcomplications (e.g., neuropathy, nephropathy, retinopathy, cataract,large blood vessel disorders, osteopenia and the like), obesity,osteoporosis, cachexia (e.g., carcinomatous cachexia, tuberculouscachexia, diabetic cachexia, hemophathic cachexia, endocrinopathiccachexia, infectious cachexia or cachexia induced by acquiredimmunodeficiency syndrome), fatty liver, hypertension, polycystic ovarysyndrome, renal disorders (e.g., glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,terminal renal disorders and the like), muscular dystrophy, myocardiacinfarction, angina pectoris, cerebral infarction, insulin resistancesyndrome, syndrome X, hyperinsulinemia-induced sensory disorder, tumors(e.g., leukemia, breast cancer, prostate cancer, skin cancer and thelike), inflammatory diseases (e.g., rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, surgical wound inflammationand swelling remedy, neuralgia, pharyngolaryngitis, cystitis, hepatitis,pneumonia, pancreatitis and the like), arterial sclerosis (e.g.,atherosclerosis and the like).

A compound according to the invention may also be employed as apharmaceutical for controlling appetite, food intake, diet and anorexia.

While the dose of a compound or a pharmaceutical composition accordingto the present invention varies depending on various factors such as thesubject to be treated, the administration route, the disease or thecondition to be treated, a compound according to the present inventionas an active ingredient may for example be given orally to an adult at asingle dose of about 0.05 to 100 mg/kg body weight, preferably about 0.1to 10 mg/kg body weight, preferably one to three times a day.

(18) Combination Use of Drugs

A compound according to the present invention may be used in combinationwith a diabetes mellitus-treating agent, a diabeticcomplication-treating agent, an antihyperlipemic agent, a hypotensiveagent, an anti-obesity agent, a diuretic, a chemotherapeutic agent, animmunotherapeutic agent and the like (hereinafter referred to as aconcomitant agent). In such case, the periods of the treatments with acompound according to the present invention and with a concomitant agentare not limited particularly, and such agents may given to a patientsimultaneously or at a certain time interval. The dose of a concomitantdrug may appropriately be determined based on the customary clinicaldose. The ratio between a compound according to the present inventionand a concomitant agent may be appropriately determined based on variousfactors such as the subject to be treated, the administration route, thedisease or the condition to be treated and the combination of the drugs.For example, when a human is treated, 1 parts by weight of a compoundaccording to the present invention is combined with 0.01 to 100 parts byweight of a concomitant agent.

Examples of an agent for treating diabetes mellitus are an insulinformulation (e.g., animal insulin formulations extracted from a pancreasof a cattle or a swine; a human insulin formulation synthesized by agene engineering technology using colibacillus and yeasts), an insulinsensitivity enhancing agent (e.g., pioglitazone hydrochloride,troglitazone, rosiglitazone and the like), an α-glycosidase inhibitor(e.g., voglibose, acarbose, miglitol, emiglitate and the like), aBiguanide (e.g., phenformin, metoformin, buformin and the like), or asulfonylurea (e.g., tolbutamide, glibenclamid, gliclazide,chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepirideand the like) as well as other insulin secretion-promoting agents (e.g.,repaglinide, senaglinide, nateglinide, mitiglinide, GLP-1 and the like),amyrin agonist (e.g. pramlintide and the like),phosphotyrosinphosphatase inhibitor (e.g. vanadic acid and the like) andthe like.

Examples of an agent for treating diabetic complications are an aldosereductase inhibitor (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidareatat, SK-860, CT-112 and the like), aneurotrophic factor (e.g., NGF, NT-3, BDNF and the like), PKC inhibitor(e.g. LY-333531 and the like), AGE inhibitor (e.g. ALT946, pimagedine,pyradoxamine, phenacylthiazolium bromide (ALT766) and the like), anactive oxygen quenching agent (e.g., thioctic acid and the like), acerebrovascular dilating agent (e.g., tiapride, mexiletene and thelike).

An antihyperlipemic agent may for example be a statin-based compoundwhich is a cholesterol synthesis inhibitor (e.g., pravastatin,simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin and thelike), a squalene synthetase inhibitor or a fibrate compound having atriglyceride-lowering effect (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate and the like) and the like.

A hypotensive agent may for example be an angiotensin converting enzymeinhibitor (e.g., captopril, enalapril, delapril and the like) or anangiotensin II antagonist (e.g., losartan, candesartan cilexetil,eprosartan, valsartan, telmisartan, irbesartan, tasosartan and the like)and the like.

An antiobesity agent may for example be a central antiobesity agent(e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine,amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorexand the like), a pancreatic lipase inhibitor (e.g., orlistat and thelike), β3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085 and the like), a peptide-based appetite-suppressingagent (e.g., leptin, CNTF and the like), a cholecystokinin agonist(e.g., lintitript, FPL-15849 and the like) and the like.

A diuretic may for example be a xanthine derivative (e.g., theobrominesodium salicylate, theobromine calcium salicylate and the like), athiazide formulation (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,bentylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazideand the like), antialdosterone formulation (e.g., spironolactone,triamterene and the like), a decarboxylase inhibitor (e.g.,acetazolamide and the like), a chlorbenzenesulfonamide formulation(e.g., chlorthalidone, mefruside, indapamide and the like), azosemide,isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and thelike.

A chemotherapeutic agent may for example be an alkylating agent (e.g.,cyclophosphamide, ifosfamide and the like), a metabolism antagonist(e.g., methotrexate, 5-fluorouracil and the like), an anticancerantibiotic (e.g., mitomycin, adriamycin and the like), avegetable-derived anticancer agent (e.g., vincristine, vindesine, taxoland the like), cisplatin, carboplatin, etoposide and the like. Amongthese substances, 5-fluorouracil derivatives such as furtulon andneofurtulon are preferred.

An immunotherapeutic agent may for example be a microorganism orbacterial component (e.g., muramyl dipeptide derivative, picibanil andthe like), a polysaccharide having immune potentiating activity (e.g.,lentinan, sizofilan, krestin and the like), a cytokine obtained by agene engineering technology (e.g., interferon, interleukin (IL) and thelike), a colony stimulating factor (e.g., granulocyte colony stimulatingfactor, erythropoetin and the like) and the like, among thesesubstances, those preferred are IL-1, IL-2, IL-12 and the like.

In addition, an agent whose cachexia improving effect has beenestablished in an animal model or at a clinical stage, such as acyclooxygenase inhibitor (e.g., indomethacin and the like) [CancerResearch, Vol.49, page 5935-5939, 1989], a progesterone derivative(e.g., megestrol acetate) [Journal of Clinical Oncology, Vol.12, page213-225, 1994], a glucosteroid (e.g., dexamethasone and the like), ametoclopramide-based agent, a tetrahydrocannabinol-based agent (supra),a lipid metabolism improving agent (e.g., eicosapentanoic acid and thelike) [British Journal of Cancer), Vol.68, page 314-318, 1993], a growthhormone, IGF-1, or an antibody against TNF-α, LIF, IL-6, oncostatin Mwhich are cachexia-inducing factors may also be employed concomitantlywith a compound according to the present invention.

The possible preferred combinations of the agents for the preventionand/or treatment of the diseases mentioned above are as follows;

(1) an insulin sensitivity enhancing agent, an insulin formulation and aBiguanide;

(2) an insulin sensitivity enhancing agent, a sulfonylurea agent and aBiguanide;

(3) an insulin sensitivity enhancing agent, a sulfonylurea agent and anα-glycosidase inhibitor;

(4) an insulin sensitivity enhancing agent, a Biguanide and anα-glycosidase inhibitor;

(5) an insulin sensitivity enhancing agent, a blood sugar reducing agentand the other kind of agents for treating diabetic complications; and

(6) an insulin sensitivity enhancing agent and any other two kinds ofagents mentioned above.

In case that the compound or the composition of the present invention isused in combination with another agent, the amount of each additionalagent can be reduced to a range which is safe in light of its adverseeffect. Especially, an insulin sensitivity enhancing agent, a biguanideand a sulfonylurea agent can be used in lower dosage than the regulardose. So, adverse effects which may be caused by these agents can besafely avoided. In addition, an agent for treating diabeticcomplications, an antihyperlipemic agent and a hypotensive agent canalso be used in lower dosages, so that adverse effects which may becaused by them can be avoided effectively.

(19) Production Methods

A method for preparing a compound according to the present invention isdescribed below. Since Compounds (I-1) and (I-2) is included in Compound(II), a method for preparing Compound (II) is described below.

Compound (II) according to the present invention may be prepared by amethod known per se, such as Method A and Method B shown below as wellas analogous methods.

wherein Z is a hydroxyl group, a halogen atom or a group represented byOSO₂R¹⁸ wherein R¹⁸ is an alkyl group having 1 to 4 carbon atoms, anaryl group having 6 to 10 carbon atoms which may be substituted with analkyl group having 1 to 4 carbon atoms, and other symbols are defined asdescribed above.

In this scheme, an alkyl group having 1 to 4 carbon atoms in “an alkylgroup having 1 to 4 carbon atoms” and “an aryl group having 6 to 10carbon atoms which may be substituted with an alkyl group having 1 to 4carbon atoms” represented by R¹⁸ may for example be methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, with methylbeing preferred.

An aryl group having 6 to 10 carbon atoms in “an aryl group having 6 to10 carbon atoms which may be substituted with an alkyl group having 1 to4 carbon atoms” represented by R¹⁸ may for example be phenyl, naphthyl,with phenyl being preferred.

In this method, Compound (III) is reacted with Compound (IV) to produceCompound (II).

When Z is hydroxy group, this reaction may be performed by a methodknown per se, for example, a method described in Synthesis, page 1(1981) or analogous methods. Thus, this reaction is performed usually inthe presence of an organic phosphorus compound or an electrophilicreagent in a solvent having no adverse effect on the reaction.

An organic phosphorus compound may for example be triphenylphosphine,tributylphosphine and the like.

An electrophilic reagent may for example be diethyl azodicarboxylate,diisopropyl azodicarboxylate, azodicarbonyldipiperazine and the like.

The amounts of an organic phosphorus compound and an electrophilicreagent to be employed were about 1 to about 5 molar equivalents toCompound (IV).

A solvent having no adverse effect on the reaction may for example be anether such as diethyl ether, tetrahydrofuran, dioxane and the like; ahalogenated hydrocarbon such as chloroform, dichloromethane and thelike; an aromatic hydrocarbon such as benzene, toluene, xylene and thelike; an amide such as N,N-dimethylformamide; a sulfoxide such asdimethyl sulfoxide and the like. These solvents may be employed as amixture in an appropriate ratio.

The reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is about 0.5 to about 20 hours.

When Z is a halogen atom or a group represented by OSO₂R¹⁸, thisreaction is performed by a standard method in the presence of a base ina solvent having no adverse effect on the reaction.

A base may for example be an alkaline metal salt such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonateand the like; an amine such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-en and the like; ametal hydride such as potassium hydride, sodium hydride and the like; analkaline metal alkoxide such as sodium methoxide, sodium ethoxide,potassium t-butoxide and the like.

The amount of a base listed above is preferably about 1 to about 5 molarequivalents to Compound (IV).

A solvent having no adverse effect on the reaction may for example be anaromatic hydrocarbon such as benzene, toluene, xylene and the like; anether such as tetrahydrofuran, dioxane and the like; a ketone such asacetone, 2-butanone and the like; a halogenated hydrocarbon such aschloroform, dichloromethane and the like; an amide such asN,N-dimethylformamide; a sufoxide such as dimethylsulfoxide and thelike. These solvents may be employed as a mixture in an appropriateratio.

The reaction temperature is usually about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is usually about 0.5 to about 20 hours.

Subsequently, Compound (II, R³═OR⁸) is hydrolyzed if necessary toproduce Compound (II″).

This hydrolyzation may be performed by a standard method, in thepresence of an acid or a base, in a water-containing solvent.

An acid may for example be hydrochloric acid, sulfuric acid, aceticacid, hydrobromic acid and the like.

A base may for example be an alkaline metal carbonate such as potassiumcarbonate, sodium carbonate and the like; a metal alkoxide such assodium methoxide and the like; an alkaline metal hydroxide such aspotassium hydroxide, sodium hydroxide, lithium hydroxide and the like.

The amount of an acid or a base to be used is usually in excess relativeto Compound (II). Preferably, the amount of an acid to be employed isabout 2 to 50 equivalents to Compound (II), while the amount of a baseto be employed is about 1.2 to about 5 equivalents to Compound (II).

A water-containing solvent may for example be a solvent mixtureconsisting of water and one or more solvents selected from the groupconsisting of an alcohol such as methanol, ethanol and the like; anether such as tetrahydrofuran, dioxane and the like; dimethylsulfoxideand acetone and the like.

The reaction temperature is usually about −20° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is usually about 0.5 to about 20 hours.

Compound (II) and Compound (II″) thus obtained may be isolated andpurified by a known separation and purification procedure such asconcentration, concentration under reduced pressure, extraction withsolvent, crystallization, recrystallization, partition andchromatography and the like.

Compound (III) and Compound (IV) employed as starting materials inMethod A described above are known compounds, and, for example, Compound(III) wherein Z is hydroxy group is described in EP-A 710659. Compound(III) is also described in EP-A 629624 (Japanese Patent ApplicationLaid-Open No. 7-53555), WO 98/03505 and the like. Compound (III) mayalso be prepared by a method analogous to those described in thesepublications.

Compound (IV) is described for example in Journal fur Praktische Chemie,Vol.311, page 370 (1969); Canadian Journal of Chemistry, Vol.48, page1948 (1970); Journal of Heterocyclic Chemistry, Vol.25, page 1283 (1988)and the like. Compound (IV) may also be prepared by a method analogousto those described in these publications.

Among Compound (II), a compound wherein R² is phenyl substituted by analiphatic hydrocarbon group and the like may be prepared also by MethodB shown below.

wherein W is an aliphatic hydrocarbon group, each optionally substitutedaromatic hydrocarbon or aromatic heterocyclic group, and other symbolsare defined as described above. “An aliphatic hydrocarbon group”represented by W may be an aliphatic hydrocarbon group exemplified as asubstituent in a hydrocarbon group and a heterocyclic group representedby R¹.

Each of an aromatic hydrocarbon group and an aromatic heterocyclic groupin “an optionally substituted aromatic hydrocarbon or aromaticheterocyclic group” represented by W may be an aromatic hydrocarbongroup and an aromatic heterocyclic group each exemplified as asubstituent on a hydrocarbon group and a heterocyclic group representedby R¹. A substituent on these aromatic hydrocarbon group and aromaticheterocyclic group may be a substituent exemplified as a substituentwhen a substituent on a hydrocarbon group and a heterocyclic grouprepresented by R¹ is a an alicyclic hydrocarbon group, an aromatichydrocarbon group, an aromatic heterocyclic group or a non-aromaticheterocyclic group.

In this method, Compound (II-1) is reacted with boronic acid compound(V) to produce Compound (II-2).

This reaction is performed by a method known per se such as a methoddescribed in Journal of Organic Chemistry, Vol.58, page 2201 (1993) orin Journal of Organic Chemistry, Vol.60, page 1060 (1995), in thepresence of a metal catalyst and a base, in a solvent having no adverseeffect on the reaction.

A metal catalyst may for example be a palladium metal a nickel metal andthe like. A palladium metal catalyst may for example betris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium and the like, and a nickel metalcatalyst may for example be 1,1′-bis(diphenylphosphino)ferrocene nickeland the like.

A base may for example be an alkaline metal bicarbonate such as sodiumbicarbonate; an alkaline metal carbonate such as sodium carbonate,potassium carbonate; an alkaline metal phosphate such as tripotassiumphosphate and the like.

The amount of a metal catalyst to be used is about 0.01 to about 1 molarequivalents, preferably about 0.05 to about 0.5 molar equivalents toCompound (II-1).

The amount of a base to be used is about 1 to about 20 molarequivalents, preferably about a to about 10 molar equivalents toCompound (II-1).

A solvent having no adverse effect on the reaction may for example be anaromatic hydrocarbon such as benzene, toluene and the like; an alcoholsuch as methanol, ethanol and the like; an ether such astetrahydrofuran, dioxane and the like; water and the like. Thesesolvents may be used in a mixture in an appropriate ratio. The types ofthe solvents may appropriately be selected depending on the types of themetal catalysts.

The amount of boric acid compound (V) employed is about 1 to about 7molar equivalents, preferably about 1 to about 5 molar equivalents toCompound (II-1).

The reaction temperature is usually about −20° C. to about 150° C.,preferably about 0° C. to about 100° C.

The reaction time is about 0.1 to about 24 hours.

Subsequently, Compound (II-2, R³═OR⁸) is hydrolyzed if desired toproduce Compound (II″-1).

This hydrolyzation may be performed similarly to the hydrolyzation inMethod A.

Compound (II-2) and (II″-1) thus obtained may be isolated and purifiedby a known separation and purification procedure such as concentration,concentration under reduced pressure, extraction with solvent,crystallization, recrystallization, partition and chromatography and thelike.

Compound (II-1) employed as a starting material in Method B describedabove may for example be produced by Method A described above. Compound(V) is a known compound described in Organic Synthesis, Vol.39, page 3(1959); Journal of American Chemical Society, Vol.94, page 4370 (1972)and the like. Compound (V) may be prepared also by a method analogous tothose described in these publications.

Compound (II) may be produced by [Method C] or [Method D] describedbelow.

In this method, the reaction between Compound (VI) and Compound (VII)results in Compound (II). This reaction may be performed by a methodknown per se. Thus, this reaction may be performed in the presence of anacid or a base in a solvent having no effects on the reaction. Such acidincludes hydrochloric acid, sulfuric acid, p-toluenesulfonic acid andthe like. Such base includes sodium carbonate, potassium carbonate,sodium acetate, (aqueous) ammonia and the like. The amount of an acid ora base to be used is usually about 1 to 10 molar equivalents to Compound(VI). A solvent having no effects on the reaction includes ethers suchas tetrahydrofuran, dioxane and the like, alcohols such as methanol,ethanol and the like, as well as dimethylsulfoxide, acetic acid, waterand the like. Any of these solvents may be used in combination with eachother at an appropriate ratio. The reaction temperature is usually about−50° C. to about 150° C., preferably about −10° C. to about 120° C.

Subsequently, if desired, Compound (II) may be hydrolyzed to formCompound (II″). This reaction may be performed similarly to thehydrolyzation in Method A.

Compound (II) and Compound (II″) thus obtained may be isolated andpurified by a known isolation and purification method such asconcentration, concentration under reduced pressure, extraction with asolvent, crystallization, recrystallization, partition, chromatographyand the like.

In this method, the reaction between Compound (VIII) and Compound (IX)results in Compound (II). This reaction may be performed similarly tothe reaction between Compound (III) and Compound (IV) in Method A.

Subsequently, if desired, Compound (II) may be hydrolyzed to formCompound (II″). This reaction may be performed similarly to thehydrolyzation in Method A.

Compound (II) and Compound (II″) thus obtained may be isolated andpurified by a known isolation and purification method such asconcentration, concentration under reduced pressure, extraction with asolvent, crystallization, recrystallization, partition, chromatographyand the like.

A compound wherein R³ is NR⁹R¹⁰ in Compound (II) may be produced byMethod E shown below.

In this method, Compound (II″) is amidated to produce Compound (II′″).This reaction may be performed by a method known per se, i.e. a directcondensation between Compound (II″) and Compound (X) using acondensation reagent (e.g., dicyclohexylcarbodiimide), or may beperformed by an appropriate reaction of a reactive derivative ofCompound (II″) with Compound (X). In such reaction, a reactivederivative of Compound (II″) includes an acid anhydride, an acid halide(acid chloride, acid bromide), imdazolide, or a mixed acid anhydride(e.g., anhydride with methyl carbonate, ethyl carbonate, isobutylcarbonate, and the like) and the like. For example, when an acid halideis employed, the reaction may be performed in the presence of a base, ina solvent having no effects on the reaction. Such base may for examplebe triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodiumbicarbonate, sodium carbonate, potassium carbonate and the like. Suchsolvent having no effects on the reaction includes a halogenatedhydrocarbon such as chloroform and dichloromethane; an aromatichydrocarbon such as benzene and toluene; an ether such astetrahydrofuran and dioxane as well as ethyl acetate and water. Any ofthese solvents may be used in combination with each other at anappropriate ratio. The amount of Compound (X) to be used is about 1 to10 molar equivalents to Compound (II″), preferably about 1 to 3 molarequivalents. The reaction temperature is usually about −30° C. to about100° C., and the reaction time ranges from about 0.5 to 20 hours. When amixed acid anhydride is employed, Compound (II″) is reacted withchlorocarbonic ester (e.g., methyl chlorocarbonate, ethylchlorocarbonate, isobutyl chlorocarbonate) in the presence of a base(e.g., triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodiumbicarbonate, sodium carbonate, potassium carbonate) and further reactedwith Compound (X). The amount of Compound (X) to be used is about 1 to10 molar equivalents to Compound (II″), preferably about 1 to 3 molarequivalents. The reaction temperature is usually about −30° C. to about100° C., and the reaction time ranges from about 0.5 to 20 hours.

Compound (II′″) thus obtained may be isolated and purified by a knownisolation and purification method such as concentration, concentrationunder reduced pressure, extraction with a solvent, crystallization,recrystallization, partition, chromatography and the like.

Compound (VI) used as a starting material in Method C may be produced bya method known per se, such as a method described in Journal of OrganicChemistry, Vol.36, page 3836 (1971) or a method analogous thereto.

Compound (IX) used as a starting material in Method D may be produced byMethod F shown below.

This method is performed similarly to the reaction between Compound(III) and Compound (IV) in Method A. The —YH moiety in Compound (XI) maybe protected prior to the condensation reaction and then deprotectedafter the reaction. A protective group which may be employed are benzylgroup, methoxymethyl group, a silyl group (e.g., trimethylsilyl group,t-butyldimethylsilyl group) and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is further detailed in the following Experiments,Reference Examples, Examples and Formulation Examples, which are notintended to restrict the present invention. In the following ReferenceExamples and Examples, a % is a % by weight unless otherwise specified.

The gene engineering procedure described in Reference Examples is inaccordance with a method described in MOLECULAR CLONING (Maniatis etal., Cold Spring Harbor Laboratory), (1989)] or in an attached protocolof a reagent.

Experiments (Hypoglycemic and Hypolipidemic Actions in Mice)

A test compound was added to a powdered diet (CE-2, Clea Japan Inc.) ata concentration of 0.01%, and the diet was given ad libitum to KKA^(y)mice (9 to 12 weeks old, 5 animals in a group), a model of obese Type IIdiabetes mellitus (non-insulin dependent diabetes mellitus), for 4 days.During this period, water was given ad libitum. Blood was sampled fromorbital venous plexus and plasma glucose and triglyceride levels weredetermined enzymatically using L type Wako Glu2 (Wako Pure Chemical Ind.Ltd.) and Iatro-MA701 TG kit (latron Laboratories Inc.) or L type WakoTG.H (Wako Pure Chemical Ind. Ltd.), respectively.

The value of each treatment group is represented as % reduction whencompared with the non-treatment group, and summarized in Table 1.

TABLE 1 Compound Hypoglycemic effect Hypotriglyceridemic effect (Examplenumber) (% reduction) (% reduction)  1 36 35  7 42 61 10 36 45 11 49 8217 49 59 1) 25 38 66 81 54 75 1) 106  46 2) 65 1), 2) 1) quantifiedusing L-type Wako TG · H 2) dosage: 0.005%

As evident from the results, a compound according to the presentinvention has excellent hypoglycemic effect and hypotriglyceridemiceffect, and is useful for the prevention and treatment of diabetesmellitus and hyperlipidemia.

Experiment (PPARγ-RXRα Heterodimer Transactivation Assay)

A PPARγ: RXRα: 4ERPP/CHO-K1 cell obtained in Reference Example 5described below was cultured in HAM F12 medium (NISSUI SEIYAKU)containing 10% Fetal Bovine serum (Life Technologies, Inc., USA) andthen inoculated to a 96-wel white plate (Corning Coaster Corporation,USA) at the density of 2×10⁴ cells/well, and cultured in a carbonate gasincubator at 37° C. overnight.

After washing a 96-well white plate with PBS (Phosphate-bufferedsaline), 90 μl of HAM F12 medium containing 0.1% fatty acid-free bovineserum albumin (BSA) and 10 μl of a test substance were added to theplate, which was then cultured in a carbonate gas incubator at 37° C.for 48 hours. After removing the medium, 40 μl of PICAGENE 7.5 (WakoPure Chemical Ind. Ltd.) was added, and after stirring, a luciferaseactivity was determined using Lumistar (BMG Labtechnologies GmBH,Germany).

An induction magnitude was calculated based on the luciferase activityof each test substance with the luciferase activity in the non-treatmentgroup being regarded as 1. The values of the test substanceconcentration and the induction magnitude were analyzed using PRISM 2.01(GraphPad Software Inc., USA) to calculate the EC₅₀ effectiveconcentration of a compound for the induction of the 50% of the maximumactivity. The results are shown in Table 2.

TABLE 2 Compound EC₅₀ (Example Number) (μM) 7 0.024 11 0.41 17 0.047 250.79 81 0.26 106 0.33

As indicated above, a compound according to the present inventionexhibited an excellent PPARγ-RXRα heterodimer ligand activity.

EXAMPLES Reference Example 1

(Human PPARγ Gene Cloning)

A human PPARγ gene was cloned using a heart cDNA (Toyobo Co., Ltd.,trade name: QUICK-clone cDNA) as a template by means of a PCR methodemploying a primer set shown below which was prepared with referring tothe DNA sequence of PPARγ gene reported by Greene et al (Gene Expr.,1995, Vol.4(4-5), page 281-299).

PAG-U: 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3′

PAG-L: 5′-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3′

The PCR procedure was performed by a hot start method using AmpliWax PCRGem 100 (TAKARA SHUZO CO., LTD.). First, 2 μl of 10×LA PCR Buffer, 3 μlof 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10μl of sterilized distilled water were mixed to obtain a bottom layersolution mixture. 1 μl of Human heart cDNA (1 ng/ml) as a template, 3 μlof 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa LATaq DNA polymerase (TAKARA SHUZO CO., LTD.) and 24.5 μl of sterilizeddistilled water were mixed to obtain a top layer solution mixture.

The bottom solution mixture received one unit of AmpliWax PCR Gem 100(TAKARA SHUZO CO., LTD.), and was treated at 70° C. for 5 minutes andthen in ice for 5 minutes, and then the top layer solution mixture wasadded to prepare the reaction mixture of PCR. A tube containing thereaction mixture was set on a thermal cycler (Perkin Elmer, USA) andtreated at 95° C. for 2 minutes. After repeating the cycle of 95° C. for15 seconds followed by 68° C. for 2 minutes further 35 times, then thetube was treated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing PPARγ gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector (TAKARASHUZO CO., LTD.) to obtain a plasmid designated as pTBT-hPPARγ.

Reference Example 2

(Human RXRα Gene Cloning)

A human RXRα gene was cloned using a kidney cDNA (Toyobo Co., Ltd.,trade name: QUICK-clone cDNA) as a template by means of a PCR methodemploying a primer set shown below which was prepared with referring tothe DNA sequence of RXRA gene reported by Mangelsdorf, D. J. et al(Nature, 1990, Vol. 345 (6272), page 224-229).

XRA-U: 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3′

XRA-L: 5′-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3′

The PCR procedure was performed by a hot start method using AmpliWax PCRGem 100 (TAKARA SHUZO CO., LTD.). First, 2 μl of 10×LA PCR Buffer, 3 μlof 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10μl of sterilized distilled water were mixed to obtain a bottom layersolution mixture. 1 μl of Human kidney cDNA (1 ng/ml) as a template, 3μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRaLA Taq DNA polymerase (TAKARA SHUZO CO., LTD.) and 24.5 μl of sterilizeddistilled water were mixed to obtain a top layer solution mixture.

The bottom solution mixture received one unit of AmpliWax PCR Gem 100(TAKARA SHUZO CO., LTD.), and was treated at 70° C. for 5 minutes andthen in ice for 5 minutes, and then the top layer solution mixture wasadded to prepare the reaction mixture of PCR. A tube containing thereaction mixture was set on a thermal cycler (Perkin Elmer, USA) andtreated at 95° C. for 2 minutes. After repeating the cycle of 95° C. for15 seconds followed by 68° C. for 2 minutes further 35 times, then thetube was treated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing RXRα gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector (TAKARASHUZO CO., LTD.) to obtain a plasmid designated as pTBT-hRXRα.

Reference Example 3

(Construction of Plasmids for Expressing Human PPARγ, RXRα)

A 7.8 kb FspI-NotI fragment of plasmid pVgRXR (Invitrogen, USA) wasligated to a 0.9 kb FspI-NotI fragment containing RXRα gene of plasmidpTBT-hRXRα obtained in Reference Example 2 to prepare plasmid pVg RXR2.Subsequently, pVgRXR2 was digested with BstXI and then treated withT4DNA polymerase (TAKARA SHUZO CO., LTD.) to obtain a blunt end. Thendigestion at KpnI gave a 6.5 kb DNA fragment.

On the other hand, plasmid pTBT-hPPARγ obtained in Reference Example 1was digested with Sal I and then treated with T4DNA polymerase (TAKARASHUZO CO., LTD.) to obtain a blunt terminal. Then digestion at KpnI gavea 1.4 kb DNA fragment containing human PPARγ gene.

Then both DNA fragments were ligated to construct plasmidpVgRXR2-hPPARγ.

Reference Example 4

(Construction of Reporter Plasmid)

A DNA fragment containing PPAR-responding element (PPRE) of an acyl CoAoxidase was prepared using the following 5′-terminal phosphorylatedsynthetic DNA.

PPRE-U: 5′-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3′

PPRE-L: 5′-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3′

First, PPRE-U and PPRE-L were annealed and inserted to Sal I site ofplasmid pBluescript SK⁺. Upon sequencing the bases of the insertedfragment, plasmid pBSS-PPRE4 in which 4 PPREs were ligated in tandem wasselected.

A HSV thymidine kinase minimum promoter (TK promoter) region was clonedusing pRL-TK vector (Promega, USA) as a template by means of a PCRmethod employing a primer set shown below which was prepared withreferring to the DNA sequence of the promoter region of thymidine kinasereported by Luckow, B et al (Nucleic Acid Res., 1987, Vol.15(13),p.5490).

TK-U: 5′-CCCAGATCTCCCCAGCGTCTTGTCATTG-3′

TK-L: 5′-TCACCATGGTCAAGCTTTTAAGCGGGTC-3′

The PCR procedure was performed by a hot start method using AmpliWax PCRGem 100 (TAKARA SHUZO CO., LTD.). First, 2 μl of 10×LA PCR Buffer, 3 μlof 2.5 mM dNTP solution, 2.5 μl of each 12.5 μM primer solution and 10μl of sterilized distilled water were mixed to obtain a bottom layersolution mixture. 1 μl of pRL-TK vector (Promega, USA) as a template, 3μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRaLA Taq DNA polymerase (TAKARA SHUZO CO., LTD.) and 24.5 μl of sterilizeddistilled water were mixed to obtain a top layer solution mixture.

The bottom solution mixture received one unit of AmpliWax PCR Gem 100(TAKARA SHUZO CO., LTD.), and was treated at 70° C. for 5 minutes andthen in ice for 5 minutes, and then the top layer solution mixture wasadded to prepare the reaction mixture of PCR. A tube containing thereaction mixture was set on a thermal cycler (Perkin Elmer, USA) andtreated at 95° C. for 2 minutes. After repeating the cycle of 95° C. for15 seconds followed by 68° C. for 2 minutes further 35 times, then thetube was treated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 140 b DNA fragment containing TK promoter wasrecovered from the gel, and then inserted into pT7 Blue-T vector (TAKARASHUZO CO., LTD.). By digesting the plasmid thus obtained with therestriction enzymes Bg1 II and NcoI, a fragment containing TK promoterwas obtained and ligated to the Bg1 II-NcoI fragment of plasmidpGL3-Basic vector (Promega, USA) to obtain plasmid pGL3-TK.

A 4.9 kb NheI-Xhol fragment of plasmid pGL3-TK thus obtained was ligatedto a 200 NheI-XhoI fragment of plasmid pBSS-PPRE4 to obtain plasmid pGL3-4ERPP-TK.

This plasmid pGL3-4ERPP-TK thus obtained was digested with BamHI (TAKARASHUZO CO., LTD.) and then treated with T4DNA polymerase (TAKARA SHUZOCO., LTD.) to form a blunt terminal, whereby obtaining a DNA fragment.

On the other hand, pGFP-C1 (Toyobo Co., Ltd.) was digested with Bsu36I(NEB) and then treated with T4DNA polymerase (TAKARA SHUZO CO., LTD.) toform a blunt terminal, whereby obtaining a 1.6 kb DNA fragment.

The both DNA fragments were ligated to construct a reporter plasmiddesignated as pGL3-4ERPP-TK neo.

Reference Examples 5

(Introduction of Human PPARγ- and RXRα-expressing Plasmid and ReporterPlasmid into CHO-K1 Cell and Establishment of Stably-transformed Cell)

A CHO-K1 cell cultured in a 750 ml tissue culture flask (Corning CostarCorporation, USA) containing HAM F12 medium (NISSUI SEIYAKU)supplemented with 10% Fetal Bovine Serum (Life Technologies, Inc., USA)was scraped by treating 0.5 g/L trypsin-0.2 g/L EDTA (ethylenediaminetetraacetic acid) (Life Technologies, Inc., USA) and the cell was washedwith PBS (phosphate-buffered saline) (Life Technologies, Inc., USA) andcentrifuged (1000 rpm, 5 minutes) and then suspended in PBS.Subsequently, a DNA was introduced into the cell under the conditionshown below using GENE PULSER (Bio-Rad Laboratories, USA).

Thus, a cuvette having an 0.4 cm gap received 8×10⁶ cells and 10 μg ofplasmid pVgRXR2-hPPARγ obtained in Reference Example 3 and 10 pg ofreporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 4 andthen subjected to electroporation at the voltage of 0.25 kV under thecapacitance of 960 μF. Subsequently, the cells were transferred into aHAM F12 medium containing 10% Fetal Bovine Serum and cultured for 24hours and then the cells were scraped again and centrifuged, and thensuspended in HAM F12 medium containing 10% Fetal Bovine Serumsupplemented with 500 μg/ml of GENETICIN (Life Technologies, Inc., USA)and 250 μg of ZEOCIN (Invitrogen, USA) and diluted to the density of 10⁴cells/ml upon inoculation to a 96-well plate (Corning CosterCorporation, USA), which was cultured in a carbonate gas incubator at37° C., whereby obtaining a GENETICIN- and ZEOCIN-resistanttransformant.

Subsequently, the transformant cell line thus obtained was cultured in a24-well plate (Corning Coster Corporation, USA) and then screened, byaddition of 10 μM Pioglitazone, for a cell line in which the luciferaseexpression was induced, i.e., PPARγ: RXRα: 4ERPP/CHO-K1 cell.

Reference Example 6

To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde(33.42 g) in methanol (150 ml)-tetrahydrofuran (30 ml), sodiumborohydride (4.31 g) was added in portions at 0° C. After stirring for30 minutes at room temperature, water was added to the reaction mixtureand the mixture was stirred for 1 hour. The crystals of4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (32.85 g, yield98%) were isolated by filtration. Recrystallization from ethylacetate-diethylether gave pale yellow crystals. m.p. 128-129° C.

Reference Example 7

To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol(5.00 g) in toluene (40 ml), thionyl chloride (1.85 ml) was added andthe mixture was stirred for 30 minutes at room temperature. Ice waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄) and concentrated to obtain4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (5.23 g, yield99%) as crystals. Recrystallization from ethyl acetate-hexane gavecolorless crystals. m.p. 108-109° C.

Reference Example 8

To a solution of 4-[2-(methyl-2-pyridylamino)ethoxy]benzaldehyde (15.0g) in methanol (70 ml), sodium borohydride (1.11 g) was added at 0° C.in portions. After stirring for 30 minutes, water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄), and then concentrated. The residue was subjected tocolumn chromatography on silica gel, and4-[2-(methyl-2-pyridylamino)ethoxy]benzylalcohol (14.3 g, yield 94%) wasobtained from a fraction eluted with ethyl acetate-hexane (1:1, v/v) asan oil.

NMR(CDCl₃) δ: 3.15(3H, s), 3.98(2H, t, J=5.5 Hz), 4.19(2H, t, J=5.5 Hz),4.61(2H, d, J=5.4 Hz), 6.50-6.59(2H, m), 6.89(2H, d, J=8.8 Hz), 7.27(2H,d, J=8.8 Hz), 7.40-7.50(1H, m), 8.13-8.18(2H, m).

Reference Example 9

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (3.41 g),3-(4-hydroxyphenyl)propanol (2.50 g), potassium carbonate (3.40 g) andN,N-dimethylformamide (25 ml) was stirred for 14 hours at 60° C. Waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄), and then concentrated. The residue wassubjected to column chromatography on silica gel, and3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (4.46 g, yield84%) was obtained from a fraction eluted with ethyl acetate-hexane (1:1,v/v) as crystals. Recrystallization from ethyl acetate-hexane gavecolorless crystals. m.p. 70-71° C.

Reference Example 10

A mixture of methyl phenylglyoxylate (25.5 g), hydroxylaminehydrochloride (11.3 g), triethylamine (22.8 ml) and methanol (300 ml)was stirred for 17 hours at 60° C. The reaction mixture wasconcentrated, and the residue was diluted with water and extracted withethyl acetate. The ethyl acetate layer was washed with water, (MgSO₄),and then concentrated. The residual crystals were recrystallized fromethyl acetatehexane to obtain methyl E-2-hydroxyimino-2-phenylacetate(3.58 g, yield 13%) as colorless crystals. m.p. 151-153° C.

Reference Example 11

The mother liquid obtained in Reference Example 10 was concentrated andthe residue was subjected to column chromatography on silica gel, andmethyl Z-2-hydroxyimino-2-phenylacetate (17.8 g, yield 64%) was obtainedas an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).

NMR(CDCl₃) δ: 3.89(3H, s), 7.34-7.48(3H, m), 7.52-7.60(2H, m), 8.51(1H,m).

Reference Example 12

To a mixture of aluminum chloride (59.0 g) and dichloromethane (500 ml),ethyl chloroglyoxylate (45.4 ml) was added dropwise at 0° C. Afterstirring for 15 minutes, anisole (40.1 ml) was added dropwise at 0° C.,and the mixture was stirred for 1.5 hours at room temperature. Thereaction mixture was poured onto ice (500 g), and the mixture wasstirred for 1 hour at room temperature. The dichloromethane layerseparated was washed with saturated aqueous sodium chloride, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel, and ethyl 4-methoxyphenylglyoxylate (43.6g, yield 60%) was obtained as an oil from a fraction eluted with ethylacetate-hexane (1:4, v/v).

NMR(CDCl₃) δ: 1.42(3H, t, J=7.1 Hz), 3.90(3H, s), 4.44(2H, q, J=7.1 Hz),6.98(2H, d, J=9.0 Hz), 8.01(2H, d, J=9.0 Hz).

Reference Example 13

A mixture of ethyl 4-methoxyphenylglyoxylate (15.0 g), hydroxylaminehydrochloride (6.00 g), sodium acetate (8.86 g) and ethanol (150 ml) washeated under reflux for 12 hours. The reaction mixture was concentrated,and the residue was diluted with water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), and thenconcentrated. The residue was subjected to column chromatography onsilica gel and ethyl Z-2-hydroxyimino-2-(4-methoxyphenyl)acetate (8.99g, yield 56%) was obtained as crystals from a fraction eluted with ethylacetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexanegave colorless crystals. m.p. 81-82° C.

Reference Example 14

From a fraction eluted following the Z-form in Reference Example 13,ethyl E-2-hydroxyimino-2-(4-methoxyphenyl)acetate (4.97 g, yield 31%)was obtained as crystals. Recrystallization from ethyl acetate-hexanegave colorless crystals. m.p. 128-129° C.

Reference Example 15

A mixture of ethyl pyruvate (9.50 g), hydroxylamine hydrochloride (6.82g), sodium acetate (10.1 g) and ethanol (150 ml) was heated under refluxfor 17 hours. The reaction mixture was concentrated, and the residue wasdiluted with water and extracted with ethyl acetate. The ethyl acetatelayer was washed with water, dried (MgSO₄), and then concentrated. Theresidual crystals were recrystallized from ethyl acetate-hexane toobtain ethyl E-2-hydroxyiminopropionate (6.33 g, yield 59%) as colorlesscrystals. m.p. 98-99° C.

Reference Example 16

A mixture of methyl 3-benzoylpropionate (15.0 g), hydroxylaminehydrochloride (6.50 g), sodium acetate (9.60 g) and methanol (150 ml)was heated under reflux for 8 hours. The reaction mixture wasconcentrated, and the residue was diluted with water and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel, and methylE-4-hydroxyimino-4-phenylbutyrate (14.7 g, yield 91%) was obtained as anoil from a fraction eluted with ethyl acetate-hexane (1:3, v/v).

NMR(CDCl₃) δ: 2.58-2.67(2H, m), 3.09-3.17(2H, m), 3.66(3H, s),7.35-7.44(3H, m), 7.56-7.67(2H, m), 8.00-8.80(1H, br s).

Reference Example 17

From a fraction eluted following the E-form in Reference Example 16,methyl Z-4-hydroxyimino-4-phenylbutyrate (1.37 g, yield 8%) was obtainedas crystals. Recrystallization from ethyl acetate-hexane gave colorlesscrystals. m.p. 76-77° C.

Reference Example 18

A mixture of ethyl 5-oxo-5-phenylpentanoate (8.00 g), hydroxylaminehydrochloride (3.03 g), sodium acetate (4.47 g) and ethanol (70 ml) washeated under reflux for 15 hours. The reaction mixture was concentrated,and the residue was diluted with water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), and thenconcentrated. The residue was subjected to column chromatography onsilica gel, and ethyl E-5-hydroxyimino-5-phenylpentanoate (7.55 g, yield88%) was obtained as crystals from a fraction eluted with ethylacetate-hexane (1:3, v/v). Recrystallization from hexane gave colorlesscrystals. m.p. 28-30° C.

Reference Example 19

To a solution of diethyl oxalate (26.3 g) in diethyl ether (400 ml), asolution of butylmagnesium chloride in tetrahydrofuran (0.90 M, 100 ml)was added dropwise at −78° C. under a nitrogen atmosphere. Afterstirring for 1 hour, the reaction mixture was allowed to warm to 0° C.,and then 1N hydrochloric acid was added. The diethyl ether layer wasseparated, washed with aqueous sodium bicarbonate and then withsaturated aqueous sodium chloride, dried (MgSO₄), and concentrated. Theresidue was dissolved in ethanol (150 ml), and hydroxylaminehydrochloride (7.50 g) and sodium acetate (11.1 g) were added. Themixture was heated under reflux for 13 hours. The reaction mixture wasconcentrated, and the residue was diluted with water and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel, and ethyl E-2-hydroxyiminohexanoate (11.0g, yield 71%) was obtained as crystals from a fraction eluted with ethylacetate-hexane (1:4, v/v). Recrystallization from hexane gave colorlesscrystals. m.p. 49-50° C.

Reference Example 20

To a solution of diethyl oxalate (19.6 g) in diethyl ether (400 ml), asolution of isopropylmagnesium bromide in tetrahydrofuran (0.67 M, 100ml) was added dropwise at −78° C. under a nitrogen atmosphere. Afterstirring for 1 hour, the reaction mixture was allowed to warm to 0° C.,and then 1N hydrochloric acid was added. A diethyl ether layer wasseparated, washed with aqueous sodium bicarbonate and then withsaturated aqueous sodium chloride, dried (MgSO₄), and concentrated. Theresidue was dissolved in ethanol (100 ml), and hydroxylaminehydrochloride (5.59 g) and sodium acetate (8.24 g) were added. Themixture was heated under reflux for 15 hours. The reaction mixture wasconcentrated, and the residue was diluted with water and extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel, and ethyl 2-hydroxyimino-3-methylbutyrate(a mixture of E- and Z-forms) was obtained from a fraction eluted withethyl acetate-hexane (1:4, v/v). Recrystallization from hexane gaveethyl E-2-hydroxyimino-3-methylbutyrate (1.91 g, yield 18%) as colorlesscrystals. m.p. 54-55° C.

NMR(CDCl₃) δ: 1.24(6H, d, J=7.0 Hz), 1.35(3H, t, J=7.1 Hz), 3.49(1H,sept, J=7.0 Hz), 4.29(2H, q, J=7.1 Hz), 9.79(1H, br s).

Reference Example 21

The mother liquid of the E-form obtained in Reference Example 20 wasconcentrated to obtain a mixture of E:Z=2.3:1 (5.69 g, yield 53%).

Z:NMR(CDCl₃) δ: 1.17(6H, d, J=6.6 Hz), 1.36(3H, t, J=7.1 Hz), 2.80(1H,sept, J=6.6 Hz), 4.36(2H, q, J=7.1 Hz), 9.75(1H, br s).

Reference Example 22

To a mixture of aluminum chloride (29.3 g) and dichloromethane (250 ml),ethyl chloroglyoxylate (22.3 ml) was added dropwise at 0° C. Afterstirring for 30 minutes, diphenyl ether (63.5 ml) was added dropwiseover 30 minutes at 0° C. followed by stirring for 2 hours, the reactionmixture was poured onto ice (250 g) and stirred for 1 hour at roomtemperature. The dichloromethane layer was separated, washed withsaturated aqueous sodium chloride, dried (MgSO₄), and then concentrated.The residue was subjected to column chromatography on silica gel, andethyl 4-phenoxyphenylglyoxylate (38.0 g, yield 70%) was obtained as anoil from a fraction eluted with ethyl acetate-hexane (1:10, v/v).

NMR(CDCl₃) δ: 1.42(3H, t, J=7.1 Hz), 4.44(2H, q, J=7.1 Hz),6.98-7.13(4H, m), 7.20-7.29(1H, m), 7.37-7.47(2H, m), 8.01(2H, d, J=9.0Hz).

Reference Example 23

A mixture of ethyl 4-phenoxyphenylglyoxylate (37.9 g), hydroxylaminehydrochloride (11.7 g), sodium acetate (17.3 g) and ethanol (200 ml) washeated under reflux for 15 hours. The reaction mixture was concentrated,and the residue was diluted with water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried (MgSO₄), and thenconcentrated. The residual crystals were recrystallized fromtoluene-hexane to obtain ethylE-2-hydroxyimino-2-(4-phenoxyphenyl)acetate (11.0 g, yield 28%) as acolorless oil. m.p. 131-132° C.

Reference Example 24

The mother liquid of the E- form obtained in Reference Example 23 wasconcentrated, and the residue was subjected to column chromatography onsilica gel to obtain ethyl Z-2-hydroxyimino-2-(4-phenoxyphenyl)acetate(23.6 g, yield 56%) as an oil from a fraction eluted with ethylacetate-hexane (1:4, v/v).

NMR(CDCl₃) δ: 1.40(3H, t, J=7.1 Hz), 4.46(2H, q, J=7.1 Hz),6.95-7.08(4H,m), 7.11-7.20(1H, m), 7.32-7.42(2H, m), 7.53(1H, d, J=8.8 Hz),8.42-8.49(1H, m).

Reference Example 25

To a mixture of aluminum chloride (41.6 g) and 1,2-dichloroethane (300ml), ethyl chloroglyoxylate (32.0 ml) was added dropwise at 0° C. Afterstirring for 30 minutes, 4-fluorobenzene (25.0 g) was added at 0° C.After stirring for 2 hours at 40° C., the reaction mixture was pouredonto ice (300 g), and the mixture was stirred for 1 hour at roomtemperature. The 1,2-dichloroethane layer was separated and washed withsaturated aqueous sodium chloride, dried (MgSO₄), and then concentrated.The residue was dissolved in ethanol (300 ml), and admixed withhydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g), andthen heated under reflux for 20 hours. The reaction mixture wasconcentrated, and the residue was diluted with water, extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel to obtain ethylZ-2-(4-fluorophenyl)-2-hydroxyiminoacetate (3.82 g, yield 6%) as an oilfrom a fraction eluted with ethyl acetate-hexane (1:3, v/v).

NMR(CDCl₃) δ: 1.40(3H, t, J=7.1 Hz), 4.46(2H, q, J=7.1 Hz),7.05-7.14(2H, m), 7.52-7.61(2H, m), 8.37(1H, s).

Reference Example 26

From a fraction eluted following the Z- form in Reference Example 25,ethyl E-2-(4-fluorophenyl)-2-hydroxyiminoacetate (2.45 g, yield 5%) wasobtained as crystals. Recrystallization from ethyl acetate-hexane gavecolorless crystals. m.p. 117-118° C.

Reference Example 27

To a mixture of aluminum chloride (41.6 g) and 1,2-dichloroethane (300ml), ethyl succinyl chloride (40.8 ml) was added dropwise at 0° C. Afterstirring for 30 minutes, 4-fluorobenzene (25.0 g) was added at 0° C.After stirring for 15 hours at 60° C., the reaction mixture was pouredonto ice (500 g), and the mixture was stirred for 1 hour at roomtemperature. The 1,2-dichloroethane layer was separated and washed withsaturated aqueous sodium chloride, dried (MgSO₄), and then concentrated.The residue was dissolved in ethanol (300 ml), and admixed withhydroxylamine hydrochloride (21.7 g) and sodium acetate (32.0 g), andthen heated under reflux for 20 hours. The reaction mixture wasconcentrated, and the residue was diluted with water, extracted withethyl acetate. The ethyl acetate layer was washed with water, dried(MgSO₄), and then concentrated. The residue was subjected to columnchromatography on silica gel to obtain ethylE-4-(4-fluorophenyl)-4-hydroxyiminobutyrate (7.45 g, yield 12%) as anoil from a fraction eluted with ethyl acetate-hexane (1:4, v/v).

NMR(CDCl₃) δ: 1.23(3H, t, J=7.1 Hz), 2.56-2.65(2H, m), 3.05-3.14(2H, m),4.11(2H, q, J=7.1 Hz), 7.01-7.14(2H, m), 7.56-7.66(2H, m), 8.05-8.40(1H,br s).

Reference Example 28

To a solution of 3-phenoxybenzylalcohol (25.0 g) and triethylamine (26.3ml) in ethyl acetate (300 ml), methanesulfonyl chloride (14.6 ml) wasadded dropwise at 0° C. After stirring for 1 hour, the reaction mixturewas washed with saturated aqueous sodium chloride, dried (MgSO₄) andconcentrated. The residue was dissolved in acetone (300 ml), admixedwith sodium iodide (37.5 g) and then stirred for 1 hour. The reactionmixture was concentrated, and the residue was diluted with water andthen extracted with ethyl acetate. The ethyl acetate layer was washedwith water, dried (MgSO₄), and then concentrated. The residue wasdissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide(7.35 g) for 15 hours at room temperature. The reaction mixture wasdiluted with ethyl acetate, washed with water, dried (MgSO₄), and thenconcentrated. The residue was subjected to column chromatography onsilica gel to obtain 3-phenoxyphenylacetonitrile (8.36 g, yield 32%) asan oil from a fraction eluted with ethyl acetate-hexane (1:7. v/v).

NMR(CDCl₃) δ: 3.72(2H, s), 6.90-7.20(6H, m), 7.28-7.43(3H, m).

Reference Example 29

To a solution of sodium ethoxide prepared from sodium (1.09 g) andethanol (20 ml), a solution of 3-phenoxyphenylacetonitrile (8.30 g) inethanol (15 ml) was added dropwise at 0° C., and then isoamyl nitrite(7.99 ml) was added dropwise. After stirring for 15 hours at roomtemperature, diethyl ether was added and the mixture was washedsequentially with 1N HCl, aqueous sodium bicarbonate and then saturatedaqueous sodium chloride. The diethyl ether layer was dried (MgSO₄),concentrated, and the residue was subjected to column chromatography onsilica gel. The crystals obtained from a fraction eluted with ethylacetate-hexane (1:4, v/v) were recrystallized with ethyl acetate-hexaneto obtain 2-hydroxyimino-2-(3-phenoxyphenyl)acetonitrile (4.25 g, yield:45%) as pale-yellow crystals. A mixture of the E- form and the Z- form.m.p. 124-125° C.

Reference Example 30

A mixture of 2-hydroxyimino-2-(3-phenoxyphenyl)acetonitrile (3.00 g),potassium hydroxide (3.40 g), ethanol (15 ml) and water (15 ml) washeated under reflux for 24 hours. The reaction mixture was acidifiedwith 1 N HCl, and extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated aqueous sodium chloride, dried (MgSO₄) andthen concentrated. The reaction mixture was dissolved in methanol (30ml), admixed with concentrated sulfuric acid (a catalytic amount), andthen heated under reflux for 24 hours. The reaction mixture was combinedwith aqueous sodium bicarbonate and extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residue was subjected to columnchromatography on silica gel to obtain methylZ-2-hydroxyimino-2-(3-phenoxyphenyl)acetate (1.14 g, yield 33%) as anoil from a fraction eluted with ethyl acetate-hexane (1:2, v/v).

NMR(CDCl₃) δ: 3.95(3H, s), 6.99-7.18(4H, m), 7.21-7.28(2H, m),7.31-7.41(3H, m), 8.33(1H, s).

Reference Example 31

From a fraction eluted following the Z- form in Reference Example 30,methyl E-2-hydroxyimino-2-(3-phenoxyphenyl)acetate (746 mg, yield 22%)was obtained as crystals. Recrystallization from ethyl acetate-hexanegave colorless crystals. m.p. 122-123° C.

Reference Example 32

A solution of 4-bromophenylmagnesium bromide prepared fromp-dibromobenzene (25.0 g), magnesium (2.43 g) and diethyl ether (250 ml)was added dropwise to a solution of diethyl oxalate (32.5 g) in diethylether (250 ml) at −78° C. under a nitrogen atmosphere. After stirringfor 1 hour, the reaction mixture was allowed to warm to 0° C., and 1NHCl was added. The diethyl ether layer separated, washed with aqueoussodium bicarbonate and with saturated aqueous sodium chloride, dried(MgSO₄), and concentrated. The residue was subjected to columnchromatography on silica gel to obtain an oil from a fraction elutedwith ethyl acetate-hexane (1:15, v/v). This oil was dissolved in ethanol(100 ml), combined with hydroxylamine hydrochloride (4.17 g) and sodiumacetate (6.15 g), and then heated under reflux for 18 hours. Thereaction mixture was concentrated, and the residue was diluted withwater and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated aqueous sodium chloride, dried (MgSO₄) and thenconcentrated. The residual crystals were recrystallized from isopropylether-hexane to obtain ethyl E-2-(4-bromophenyl)-2-hydroxyiminoacetate(4.31 g, yield 16%) as crystals. m.p. 163-164° C.

Reference Example 33

From a fraction eluted following the E- form in Reference Example 32,ethyl Z-2-(bromophenyl)-2-hydroxyiminoacetate (5.31 g, yield 20%) wasobtained as an oil.

NMR(CDCl₃) δ: 1.40(3H, t, J=7.1 Hz), 4.55(2H, q, J=7.1 Hz)), 7.43(2H, d,J=8.6 Hz), 7.54(2H, d, J=8.6 Hz), 8.47(1H, s).

Reference Example 34

To a solution of sodium ethoxide prepared from sodium (7.22 g) andethanol (400 ml), ethyl phenylacetate (25.8 g) and diethyl oxalate (45.9g) were added and the mixture was stirred for 1.5 hours at 70° C. withseparating ethanol. The reaction mixture was combined with ethyl acetate(500 ml) and 1N HCl (350 ml), and the ethyl acetate layer was separated.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residue was dissolvedin dimethyl sulfoxide (150 ml)-water (15 ml), admixed with sodiumchloride (9.18 g), and then the mixture was stirred for 1.5 hours at130° C. The reaction mixture was diluted with water and extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄), and then concentrated. The residue wasdissolved in ethanol (100 ml), admixed with hydroxylamine (3.34 g) andsodium acetate (4.92 g), and then the mixture was heated under refluxfor 17 hours. The reaction mixture was concentrated, and the residue wascombined with water, and then extracted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium chloride, dried(MgSO₄) and then concentrated. The residue was subjected to columnchromatography on silica gel to obtain ethylE-2-hydroxyimino-3-phenylpropionate (6.94 g, yield 21%) as crystals froma fraction eluted with ethyl acetate-hexane (1:3, v/v).Recrystallization from ethyl acetate-hexane gave colorless crystals.m.p. 54-55° C.

Reference Example 35

n-Butyllithium (1.6N hexane solution, 108 ml) was added dropwise to adiethyl ether solution (400 ml) of 3-bromopyridine (25.7 g) at −78° C.over 1 hour under nitrogen atmosphere. After stirring for 30 minutes, adiethyl ether solution (100 ml) of diethyl oxalate (28.6 g) was addeddropwise thereto at −78° C. over 1 hour. The reaction mixture wasfurther mixed for 30 minutes, allowed to warm to 0° C., and 1Nhydrochloric acid (200 ml) was added thereto. After stirring for 30minutes, sodium bicarbonate was added thereto to neutralize the reactionmixture. The organic layer was separated, washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtain ethyl3-pyridylglyoxylate (13.1 g, yield 45%) from an ethyl acetate-hexane(1:1, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.45 (3H, t, J=7.1 Hz), 4.48 (2H, q, J=7.1 Hz), 7.45-7.53(1H, m), 8.33-8.41 (1H, m), 8.85-8.90 (1H, m), 9.26-9.29 (1H, m).

Reference Example 36

A mixture of ethyl 3-pyridylglyoxylate (6.00 g), hydroxylaminehydrochloride (2.79 g), sodium acetate (4.13 g) and ethanol (80 ml) washeated to reflux for 15 hours. The reaction mixture was concentrated,water was added to the residue, and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The remaining crystalswere recrystallized from ethyl acetate to obtain ethylE-2-hydroxyimino-2-(3-pyridyl)-acetate (3.30 g, yield 51%) as colorlesscrystals. m.p. 172-173° C.

Reference Example 37

The mother liquid of Reference Example 36 was concentrated and theresidue was subjected to silica gel chromatography to obtain thecrystals from an ethyl acetate-hexane (3:2, v/v)-eluted fraction. Thecrystals were recrystallized from ethyl acetate-hexane to obtain ethylZ-2-hydroxyimino-2-(3-pyridyl)acetate (1.55 g, yield 24%) as colorlesscrystals. m.p. 137-138° C.

Reference Example 38

To a solution of sodium ethoxide prepared from sodium (2.51 g) andethanol (40 ml) was added dropwise a solution of2-(3-bromophenyl)acetonitrile (17.8 g) in ethanol (30 ml) at 0° C., andthen isoamyl nitrite (18.3 ml) was added dropwise thereto. Afterstirring at room temperature for 18 hours, diethyl ether was added, andwashed successively with 1N hydrochloric acid, an aqueous sodiumbicarbonate solution, and an aqueous saturated solution of sodiumchloride. The diethyl ether layer was dried (MgSO₄), concentrated, andthe residue was subjected to silica gel chromatography to obtain2-(3-bromophenyl)-2-(hydroxyimino)acetonitrile (19.9 g, yield 97%) as anorange paste from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.Recrystallization from ethyl acetate-hexane gave orange crystals. m.p.91-93° C.

Reference Example 39

A 1,2-dibromoethane solution (12 ml) of bromine (5.43 ml) was addeddropwise over 3 hours while refluxing to a 1,2-dibromoethane solution(40 ml) of 3-methylbenzophenone (20.0 g). After heating to reflux for 30minutes, the reaction mixture was concentrated. The residue wasdissolved in dimethyl sulfoxide (100 ml) and stirred with sodium cyanide(7.50 g) at room temperature for 2 hours. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain 2-(3-benzoylphenyl)acetonitrile (13.8 g, yield61%) as a yellow oil from an ethyl acetate-hexane (1:3, v/v)-elutedfraction.

NMR(CDCl₃) δ: 3.84 (2H, s), 7.46-7.68 (5H, m), 7.73-7.83 (4H, m).

Reference Example 40

To a solution of sodium ethoxide prepared from sodium (1.70 g) andethanol (40 ml) was added dropwise a solution of2-(3-benzoylphenyl)acetonitrile (13.6 g) in ethanol (30 ml) at 0° C.,and then isoamyl nitrite (12.4 ml) was added dropwise. After stirring atroom temperature for 15 hours, the reaction mixture was diluted withethyl acetate and washed successively with 1N hydrochloric acid and anaqueous saturated solution of sodium chloride. The ethyl acetate layerwas dried (MgSO₄) and concentrated to obtain2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (15.2 g, yield 99%) ascrystals. Recrystallization from ethyl acetate-hexane gave an isomer of2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile as colorless crystals.m.p. 175-176° C.

Reference Example 41

The mother liquid of Reference Example 40 was concentrated, and theresidue was recrystallized from ethyl acetate-hexane to obtain anotherisomer of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile as colorlesscrystals. m.p. 147-148° C.

Reference Example 42

A mixture of 2-(3-bromophenyl)-2-(hydroxyimino)acetonitrile (19.0 g), 4Naqueous solution of potassium hydroxide (100 ml) and 2-methoxyethanol(100 ml) was heated under reflux for 4 hours. The reaction mixture wascooled to room temperature, 1N hydrochloric acid was added to make thesolution acidic and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was dissolved in ethanol(200 ml) and concentrated sulfuric acid (catalytic amount) was added.The reaction mixture was heated under reflux for 48 hours, cooled toroom temperature, poured into an aqueous saturated solution of sodiumbicarbonate and extracted with ethyl acetate. The ethyl acetate layerwas washed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethylZ-2-(3-bromophenyl)-2-(hydroxyimino)acetate (3.31 g, yield 14%) as apale-brown oil from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.41 (3H, t, J=7.1 Hz), 4.47 (2H, q, J=7.1 Hz), 7.23-7.32(1H, m), 7.45-7.60 (2H, m), 7.72-7.75 (1H, m), 8.56 (1H, br s).

Reference Example 43

Ethyl E-2-(3-bromophenyl)-2-(hydroxyimino)acetate was obtained ascrystals from a fraction which eluted following the Z- isomer inReference Example 42. Recrystallization from ethyl acetate-hexane gavecolorless crystals (1.52 g, yield 7%). m.p. 113-114° C.

Reference Example 44

A mixture of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (14.5 g),4N aqueous solution of potassium hydroxide (80 ml) and ethanol (80 ml)was heated under reflux for 20 hours. The reaction mixture was cooled toroom temperature, 1N hydrochloric acid was added to make the solutionacidic and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was dissolved in ethanol (150 ml)and concentrated sulfuric acid (catalytic amount) was added. Thereaction mixture was heated under reflux for 15 hours, cooled to roomtemperature, poured into an aqueous saturated solution of sodiumbicarbonate and extracted with ethyl acetate. The ethyl acetate layerwas washed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethylZ-2-(3-benzoylphenyl)-2-(hydroxyimino)acetate (2.48 g, yield 14%) as apale-brown oil from an ethyl acetate-hexane (1:2, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 4.45 (2H, q, J=7.1 Hz), 7.30-7.66(4H, m), 7.70-8.00 (5H, m), 8.66 (1H, br s).

Reference Example 45

Ethyl E-2-(3-benzoylphenyl)-2-(hydroxyimino)acetate was obtained ascrystals from a fraction which eluted following the Z- isomer inReference Example 44. Recrystallization from ethyl acetate-hexane gaveorange crystals (1.70 g, yield 10%). m.p. 109-110° C.

Reference Example 46

To a mixture of aluminum chloride (14.7 g) and dichloromethane (120 ml)was added dropwise ethyl succinyl chloride (14.3 ml) at 0° C. Afterstirring for 30 minutes, this was added dropwise to a solution ofdiphenyl ether (34.0 g) in dichloromethane (50 ml) at 0° C. Afterstirring for 3 hours, the reaction mixture was poured onto ice (200 g),and stirred at room temperature for 1 hour. The dichloromethane layerwas separated, washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was dissolved inethanol (150 ml), and hydroxylamine hydrochloride (8.34 g) and sodiumacetate (12.3 g) were added. After refluxing for 15 hours, the reactionmixture was concentrated, water was added to the residue and extractedwith ethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtain ethylE-4-(hydroxyimino)-4-(4-phenoxyphenyl)butyrate (10.5 g, yield 34%) as acolorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.23 (3H, t, J=7.1 Hz), 2.57-2.66 (2H, m), 3.06-3.15 (2H,m), 4.12 (2H, q, J=7.1 Hz), 6.97-7.19 (5H, m), 7.31-7.42 (2H, m), 7.59(2H, d, J=9.2 Hz), 7.90-8.60 (1H, br).

Reference Example 47

A mixture of 2-chloropyrimidine (20.8 g) and 2-(methylamino)ethanol (180ml) was heated at 120° C. for 15 hours and concentrated. The residue wasdissolved in ethyl acetate, washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasdistilled under reduced pressure to obtain2-(methyl-2-pyrimidylamino)ethanol (24.6 g, yield 88%) as a colorlessoil. b.p. 130-132° C./1-1.5 mmHg

Reference Example 48

Sodium hydride (60% in oil, 4.40 g) was added to a solution of2-(methyl-2-pyrimidylamino)ethanol (15.3 g) in N,N-dimethylformamide(400 ml) at room temperature under nitrogen atmosphere and stirred for 1hour. A solution of 4-fluorobenzaldehyde (13.6 g) inN,N-dimethylformamide (100 ml) was added dropwise and stirred at roomtemperature for 15 hours. The reaction mixture was poured onto ice (200g) and concentrated. The residue was dissolved in ethyl acetate, washedwith an aqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (18.4 g, yield72%) as crystals from an ethyl acetate-hexane (1:1, v/v)-elutedfraction. Recrystallization from ethyl acetate-hexane gave colorlesscrystals. m.p. 74-75° C.

Reference Example 49

To a solution of 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzaldehyde (16.6g) in methanol (40 ml)-tetrahydrofuran (40 ml) was added sodiumborohydride (1.22 g) in portions at 0° C. After stirring for 1 hour,water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theresidual crystals were recrystallized from ethyl acetate-hexane toobtain 4-[2-(methyl-2-pyrimidylamino)ethoxy]benzylalcohol (15.3 g, yield91%) as colorless crystals. m.p. 73-74° C.

Reference Example 50

A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(5.00 g), N-hydroxyphthalimide (2.59 g), potassium carbonate (4.40 g)and N,N-dimethylformamide (50 ml) was stirred at room temperature for 20hours, and water (500 ml) was added. The resultant crystals werefiltered, and washed with water to obtainN-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (6.49 g,yield 93%) as colorless crystals. m.p. 155-156° C.

Reference Example 51

Sodium hydride (60% in oil, 649 mg) was added to a solution of2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (3.00 g) inN,N-dimethylformamide (60 ml) at room temperature under nitrogenatmosphere and stirred at room temperature for 1 hour. A solution of4-fluorobenzaldehyde (2.02 g) in N,N-dimethylformamide (15 ml) was addeddropwise and stirred at room temperature for 12 hours. The reactionmixture was poured onto ice (50 g) and concentrated. The residue wasdissolved in ethyl acetate, washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain an oil from an ethylacetate-hexane (1:4, v/v)-eluted fraction. This was dissolved intetrahydrofuran (20 ml) and methanol (20 ml), and sodium borohydride(321 mg) was added at 0° C., and then stirred for 1 hour. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasdissolved in toluene (20 ml), thionyl chloride (0.888 ml) was added at0° C. and stirred for 1 hour. The reaction mixture was concentrated, andthe remaining crystals were recrystallized from ethyl acetate-hexane toobtain 4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (2.51g, yield 52%) as pale-yellow crystals. m.p. 93-94° C.

Reference Example 52

Hydrazine monohydrate (1.15 ml) was added to a solution ofN-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (5.22 g)in ethanol (40 ml)-tetrahydrofuran (40 ml) and heated under reflux for 3hours. The reaction mixture was cooled to room temperature, diluted withan aqueous solution of potassium carbonate and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (3.32 g,yield 90%) as colorless crystals. m.p. 68-69° C.

Reference Example 53

A mixture of 5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridinehydrochloride (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassiumcarbonate (6.14 g) and N,N-dimethylformamide (30 ml) was stirred at roomtemperature for 15 hours, poured into water and extracted with ethylacetate. The ethyl acetate layer was washed with an queous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.55g, yield 98%) as colorless crystals. m.p. 126-130° C.

Reference Example 54

Sodium borohydride (232 mg) was added to a solution of4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.52 g) inmethanol (10 ml)-tetrahydrofuran (50 ml) at 0° C. After stirring for 1hour, water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate to obtain4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzylalcohol (2.34 g,yield 66%) as colorless crystals. m.p. 169-171° C.

Reference Example 55

Thionyl chloride (0.597 ml) was added dropwise to a mixture of4-(5-chloroimidazo[1,2-a]pyridine-2-ylmethoxy)benzylalcohol (1.97 g),triethylamine (1.15 ml) and toluene (50 ml) at 0° C. After stirring for1 hour, water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain 5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-a]pyridine(1.10 g, yield 52%) as colorless crystals. m.p. 114-115° C.

Reference Example 56

Carbonyldiimidazole (7.25 g) was added to a solution of2-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (200 ml) at 0° C.After stirring at room temperature for 2 hours, the mixture was addeddropwise to a solution of lithiated tert-butyl acetate prepared fromtert-butyl acetate (17.5 ml) and lithium diisopropylamide (2Ntetrahydrofuran solution, 65 ml) at −78° C. over 1 hour. After stirringfor 15 minutes, 1N hydrochloric acid (250 ml) was added and extractedwith ethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtain an oilfrom an ethyl acetate-hexane(1:4, v/v)-eluted fraction. This wasdissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil,1.06 g) was added at 0° C., and then the reaction mixture was stirredfor 10 minutes. Further ethyl bromoacetate (2.00 ml) was added, stirredat 0° C. for 8 hours, 0.1N hydrochloric acid (300 ml) was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain an oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.This was dissolved in toluene (200 ml), and p-toluenesulfonic acid (2.00g) was added, and then the reaction mixture was stirred at 80° C. for 20hours. An aqueous saturated solution of sodium bicarbonate was added tothe reaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethyl 4-oxo-4-(2-pyridyl)butyrate (1.56 g,yield 19%) from an ethyl acetate-hexane (1:2, v/v)-eluted fraction as acolorless oil.

NMR(CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 2.76 (2H, d, J=6.7 Hz), 3.57 (2H,d, J=6.7 Hz), 4.16 (2H, q, J=7.1 Hz), 7.48 (1H, dd, J=4.8, 7.6 Hz), 7.84(1H, dt, J=1.8, 7.6 Hz), 8.05 (1H, d, J=7.6 Hz), 8.69 (1H, dd, J=1.8,4.8 Hz).

Reference Example 57

Oxalyl chloride (4.47 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution of 2-furancarboxylic acid (5.00 g) intetrahydrofuran (50 ml) at room temperature, which was stirred at roomtemperature for 1 hour, followed by concentration. The residue wasdissolved in tetrahydrofuran (20 ml) and added dropwise to a solution oflithiated tert-butyl acetate prepared from tert-butyl acetate (19.3 ml)and lithium diisopropylamide (2N tetrahydrofuran solution, 72 ml) −78°C. over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid (250ml) was added and extracted with ethyl acetate. The ethyl acetate layerwas washed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain crystals from an ethyl acetate-hexane (1:5,v/v)-eluted fraction. Recrystallization from ethyl acetate-hexane gavetert-butyl 3-(2-furyl)-3-oxopropionate (3.28 g, yield 35%) as colorlesscrystals. m.p. 74-75° C.

Reference Example 58

Sodium hydride (60% in oil, 629 mg) was added to a solution oftert-butyl 3-(2-furyl)-3-oxopropionate (3.01 g) in tetrahydrofuran (80ml) at 0° C. and stirred for 10 minutes. Ethyl bromoacetate (1.51 ml)was added to the mixture, and then the resultant was stirred at roomtemperature for 4 hours, 0.1N hydrochloric acid (200 ml) was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgS0 ₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain an oil from and ethyl acetate-hexane (1:5, v/v)-eluted fraction.This was dissolved in toluene (150 ml), and trifluoroacetic acid (2.64ml) was added, and then the reaction mixture was stirred at 90° C. for 6hours. An aqueous saturated solution of sodium bicarbonate was added tothe reaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethyl 4-(2-furyl)-4-oxobutyrate (2.22 g, yield79%) as a colorless oil from an ethyl acetate-hexane (1:3, v/v)-elutedfraction.

NMR(CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.74 (2H, t, J=6.7 Hz), 3.18 (2H,t, J=6.7 Hz), 4.15 (2H, q, J=7.1 Hz), 6.53-6.57 (1H, m), 7.23 (1H, d,J=3.6 Hz), 7.59 (1H, d, J=1.8 Hz).

Reference Example 59

Carbonyldiimidazole (7.25 g) was added to a solution of nicotinic acid(5.00 g) in tetrahydrofuran (100 ml) at 0° C. After stirring at roomtemperature for 2 hours, the mixture was added dropwise to a solution oflithiated tert-butyl acetate prepared from tert-butyl acetate (17.5 ml)and lithium diisopropylamide (2N tetrahydrofuran solution, 65 ml) at −78° C. over 1 hour. After stirring for 15 minutes, 1N hydrochloric acid(250 ml) was added and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was dissolved intetrahydrofuran (100 ml), sodium hydride (60% in oil, 1.38 g) was addedat 0° C. and stirred for 10 minutes. Ethyl bromoacetate (3.33 ml) wasadded to the mixture, and the reaction mixture was stirred at roomtemperature for 3 hours, 0.1N hydrochloric acid (350 ml) was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.This oil was dissolved in toluene (150 ml), and trifluoroacetic acid(7.68 ml) was added and then the resultant mixture was stirred at 90° C.for 4 hours. An aqueous saturated solution of sodium bicarbonate wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethyl4-oxo-4-(3-pyridyl)butyrate (3.39 g, yield 38%) as a colorless oil froman ethyl acetate-hexane (2:1, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 2.79 (2H, t, J=6.6 Hz), 3.33 (2H,t, J=6.6 Hz), 4.17 (2H, q, J=7.1 Hz), 7.43 (1H, dd, J=4.8, 8.0 Hz),8.23-8.30 (1H, m), 8.80 (1H, dd, J=1.6, 4.8 Hz), 9.22 (1H, d, J=2.2 Hz).

Reference Example 60

Carbonyldiimidazole (7.25 g) was added to a solution of4-pyridinecarboxylic acid (5.00 g) in tetrahydrofuran (80 ml) at 0° C.After stirring at room temperature for 2 hours, the mixture was addeddropwise to a solution of lithiated tert-butyl acetate prepared fromtert-butyl acetate (17.5 ml) and lithium diisopropylamide (2Ntetrahydrofuran solution, 65 ml) at −78 ° C. over 1 hour. After stirringfor 15 minutes, 1N hydrochloric acid (250 ml) was added and extractedwith ethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtain an oilfrom an ethyl acetate-hexane (2:3, v/v)-eluted fraction. This oil wasdissolved in tetrahydrofuran (100 ml), and sodium hydride (60% in oil,1.16 g) was added at 0° C., and then the reaction mixture was stirredfor 10 minutes. Ethyl bromoacetate (2.88 ml) was added to the mixture,and the resultant mixture was stirred at room temperature for 24 hours,0.1N hydrochloric acid (300 ml) was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain an oil from anethyl acetate-hexane (1:1, v/v)-eluted fraction. This oil was dissolvedin toluene (120 ml), and stirred with trifluoroacetic acid (5.64 ml) at90° C. for 6 hours. An aqueous saturated solution of sodium bicarbonatewas added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethyl4-oxo-4-(4-pyridyl)butyrate (2.61 g, yield 31%) from an ethylacetate-hexane (2:1, v/v)-eluted fraction as a pale brown oil.

NMR(CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.78 (2H, t, J=6.5 Hz), 3.30 (2H,t, J=6.5 Hz), 4.17 (2H, q, J=7.1 Hz), 7.76 (2H, d, J=6.2 Hz), 8.83 (2H,d, J=6.2 Hz).

Reference Example 61

Sodium borohydride (1.18 g) was added to a solution of3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (18.3 g) in methanol(50 ml)-tetrahydrofuran (100 ml) in portions at 0° C. After stirring for30 minutes, water was added to the reaction mixture and extracted withethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The remaining crystals were recrystallized from ethyl acetate-hexane toobtain 3-(5-methy-12-phenyl-4-oxazolylmethoxy)benzylalcohol (15.5 g,yield 84%) as colorless crystals. m.p. 101-102° C.

Reference Example 62

Thionyl chloride (4.45 ml) was added dropwise to a mixture of3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.0 g) andtoluene (200 ml) at 0° C. After stirring at room temperature for 1 hour,water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (13.4 g,yield 84%) as pale-yellow crystals. m.p. 79-80° C.

Reference Example 63

A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(8.00 g), N-hydroxyphthalimide (4.13 g), potassium carbonate (7.05 g)and N,N-dimethylforrnamide (80 ml) was stirred at room temperature for20 hours and water (800 ml) was added. The resultant crystals werefiltered and washed with water to obtainN-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (10.1 g,yield 90%) as pale-brown crystals. m.p. 146-147° C.

Reference Example 64

Hydrazine monohydrate (0.661 ml) was added to a solution ofN-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (3.00 g)in ethanol (25 ml)-tetrahydrofuran (25 ml) and heated under reflux for 3hours. The reaction mixture was cooled to room temperature, an aqueoussolution of potassium carbonate was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (2.04 g,yield 97%) as pale-yellow crystals. m.p. 81-82° C.

Reference Example 65

A mixture of 2-aminopyridine (12.5 g), 1,3-dichloro-2-propanone (17.7 g)and acetonitrile (100 ml) was heated under reflux for 2 hours andconcentrated. An aqueous saturated solution of sodium bicarbonate wasadded to the residue and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain crystals from an ethyl acetate-hexane (3:2,v/v)-eluted fraction. Recrystallization from ethyl acetate-hexane gave2-chloromethylimidazo[1,2-a]pyridine (7.52 g, yield 34%) as pale-yellowcrystals. m.p. 93-94° C.

Reference Example 66

Oxalyl chloride (0.508 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution of 6-oxo-6-phenylhexanoic acid (1.00 g) intetrahydrofuran (15 ml) at room temperature, which was stirred at roomtemperature for 1 hour and concentrated. The residue was dissolved inethyl acetate (25 ml) and added dropwise to a stirred mixture of 25%aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0° C. Afterstirring at room temperature for 2 hours, water (200 ml) was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The remaining crystals were recrystallized from ethylacetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, yield 89%) ascolorless crystals. m.p. 113-114° C.

Reference Example 67

A mixture of acetophenone (25.0 ml) and diethyl oxalate (58.3 ml) wasadded to a solution of sodium ethoxide prepared from sodium (9.85 g) andethanol (300 ml) and heated under reflux for 1 hour. The reactionmixture was concentrated, diluted with 1N hydrochloric acid (450 ml) andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was dissolved in ethanol (250 ml), andhydroxylamine hydrochloride (44.6 g) was added, and then the reactionmixture was refluxed for 1 hour. The reaction mixture was concentrated,water was added to the residue and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The remaining crystalswere recrystallized from ethyl acetate-hexane to obtain ethyl5-phenylisoxazole-3-carboxylate (31.5 g, yield 70%) as pale-browncrystals. m.p. 46-47° C.

Reference Example 68

Triethylamine (7.28 ml) was added to a solution of α-chlorobenzaldehydeoxime (4.04 g) and 2-propyn-1-ol (1.66 ml) in tetrahydrofuran (130 ml)and stirred at room temperature for 4 days. Water was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The remaining crystals wererecrystallized from ethyl acetate-hexane to obtain(3-phenyl-5-isoxazolyl)methanol (3.42 g, yield 75%) as colorlesscrystals. m.p. 48-49° C.

Reference Example 69

A solution of ethyl 5-phenylisoxazole-3-carboxylate (20.0 g) in diethylether (50 ml) was added dropwise to a mixture of lithium aluminiumhydride (2.62 g) in diethyl ether (50 ml) at 0° C. After stirring for 1hour, water was added to the reaction mixture carefully, followed byaddition of 1N hydrochloric acid (200 ml) and extraction with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theremaining crystals were recrystallized from ethyl acetate-hexane toobtain (5-phenyl-3-isoxazolyl)methanol (15.2 g, yield 94%) as pale-browncrystals. m.p. 101-102° C.

Reference Example 70

Thionyl chloride (2.41 ml) was added to a solution of(3-phenyl-5-isoxazolyl)methanol (2.89 g) in toluene (10 ml) and stirredat 60° C. for 1 hour. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The remaining crystals were recrystallized from ethylacetate-hexane to obtain 5-(chloromethyl)-3-phenylisoxazole (2.75 g,yield 86%) as pale-brown crystals. m.p. 69-70° C.

Reference Example 71

Thionyl chloride (7.55 ml) was added to a solution of(5-phenyl-3-isoxazolyl)methanol (12.1 g) in toluene (50 ml) and stirredat 80° C. for 3 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The remaining crystals were recrystallized from ethylacetate-hexane to obtain 3-(chloromethyl)-5-phenylisoxazole (11.8 g,yield 88%) as pale-yellow crystals. m.p. 46-47° C.

Reference Example 72

Chloromethyl methyl ether (34.2 ml) was added to a mixture of4-hydroxybenzaldehyde (50.0 g), potassium carbonate (84.9 g) andN,N-dimethylformaldehyde (150 ml) at 0° C. and stirred at roomtemperature for 11 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was dissolved in tetrahydrofuran (300 ml) andmethanol (50 ml) and sodium borohydride (7.76 g) was added in portionsat 0° C. After stirring for 30 minutes, water was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain 4-methoxymethoxybenzylalcohol (56.7 g, yield82%) as a colorless oil from an ethyl acetate-hexane (2:3, v/v) elutedfraction.

NMR(CDCl₃) δ: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2H, s), 7.03 (2H, d,J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz).

Reference Example 73

Diethyl azodicarboxylate (40% toluene solution, 142 g) was addeddropwise to a solution of 4-methoxymethoxybenzylalcohol (50.0 g),N-hydroxyphthalimide (44.1 g) and triphenylphosphine (83.7 g) intetrahydrofuran (900 ml) at room temperature and stirred for 1 hour. Thereaction mixture was concentrated. In order to remove triphenylphosphineoxide, the residue was subjected to silica gel chromatography to obtaincrystals from an ethyl acetate-hexane (1:5, v/v)-eluted fraction. Thecrystals were washed with ethyl acetate-hexane (1:5, v/v) and thendissolved in tetrahydrofuran (200 ml) and ethanol (50 ml). To thissolution was added hydrazine monohydrate (33.7 ml) and heated underreflux for 3 hours. The reaction mixture was cooled to room temperature,an aqueous solution of potassium carbonate was added and extracted withethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.Isopropyl ether was added to the residue and filtered to removeinsolubles. The filtrate was concentrated to obtain4-methoxymethoxybenzyloxyamine (28.9 g, yield 58%) as a colorless oil.

NMR(CDCl₃) δ: 3.48 (3H, s), 4.63 (2H, s), 5.18 (2H, s), 7.04 (2H, d,J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz).

Reference Example 74

A mixture of 4-methoxymethoxybenzyloxyamine (4.99 g), methyl4-oxo-4-phenylbutyrate (5.71 g), acetic acid (5.10 ml), sodium acetate(4.87 g) and methanol (200 ml) was heated under reflux for 15 hours. Thereaction mixture was cooled to room temperature, dilute hydrochloricacid was added to the residue and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasdissolved in tetrahydrofuran (50 ml) and methanol (5 ml). To thissolution was added 1N hydrochloric acid (10 ml) and heated under refluxfor 3 hours. The reaction mixture was cooled to room temperature, waterwas added and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (4.24 g, yield 50%) as acolorless oil from an ethyl acetate-hexane (2:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.63 (3H, s),4.97-5.05 (1H, m), 5.14 (2H, s), 6.82 (2H, d, J=8.8 Hz), 7.25-7.38 (5H,m), 7.59-7.65 (2H, m).

Reference Example 75

Sodium hydride (60% in oil, 2.18 g) was added to a solution of ethylbenzoylacetate (10.0 g) in N,N-dimethylformamide (100 ml) at 0° C. andstirred for 30 minutes. To this mixture was added methyl iodide (3.89ml) and stirred for 1 hour. Sodium hydride (60% in oil, 2.18 g) wasadded to the mixture, and stirred for 30 minutes. Further, methyl iodide(3.89 ml) was added and stirred for 1 hour. The reaction mixture waspoured into 0.05N hydrochloric acid (1000 ml) and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain ethyl2,2-dimethyl-3-oxo-phenylpropionate (7.37 g, yield 64%) as a colorlessoil from an ethyl acetate-hexane (1:20, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.05 (3H, t, J=7.1 Hz), 1.55 (6H, s), 4.12 (2H, q, J=7.1Hz), 7.37-7.58 (3H, m), 7.81-7.87 (2H, m).

Reference Example 76

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (15.6 g), methyl4-hydroxyphenylacetate (12.5 g), potassium carbonate (20.8 g) andN,N-dimethylformamide (80 ml) was stirred at room temperature for 18hours. Water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain methyl4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetate (23.8 g, yield 94%)as crystals from an ethyl acetate-hexane (1:4, v/v)-eluted fraction. Thecrystals were recrystallized from ethyl acetate-hexane to obtaincolorless crystals. m.p. 74-75° C.

Reference Example 77

A mixture of methyl 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetate(23.2 g), lithium hydroxide monohydrate (4.33 g), tetrahydrofuran (100ml), water (60 ml) and methanol (40 ml) was stirred at room temperaturefor 1 hour. 1N hydrochloric acid (103 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The remaining crystals were recrystallizedfrom acetone to obtain4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylacetic acid (21.9 g, yield98%). m.p. 181-183° C.

Reference Example 78

Aluminium chloride (2.58 g) was added to a mixture of methyl8-chloro-8-oxooctanoate (2.00 g) and anisole (5 ml) at 0° C. Afterstirring at room temperature for 14 hours, the reaction mixture waspoured onto ice (50 g), stirred at room temperature for 1 hour andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methyl 8-(4-methoxyphenyl)-8-oxooctanoate (2.37 g, yield 88%) ascrystals. The crystals were recrystallized from ethyl acetate-hexane toobtain colorless crystals. m.p. 57-58° C.

Reference Example 79

Tert-butyldimethylsilyl chloride (24.1 g) was added to a mixture of4-hydroxybenzaldehyde (17.8 g), imidazole (19.8 g) andN,N-dimethylformamide (100 ml). After stirring at room temperature for 2hours, water was added and extracted with ethyl acetate. The ethylacetate layer was washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was dissolved intetrahydrofuran (300 ml) and methanol (40 ml), and then sodiumborohydride (11.1 g) was added in portions at 0° C. After stirring for30 minutes, water was added and extracted with ethyl acetate. The ethylacetate layer was washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel chromatography to obtain4-(tert-butyldimethylsilyloxy)benzylalcohol (27.7 g, yield 79%) as acolorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 0.19 (6H, s), 0.98 (9H, s), 4.61 (2H, s), 6.83 (2H, d,J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz).

Reference Example 80

Diethyl azodicarboxylate (40% toluene solution, 54.0 g) was addeddropwise to a solution of 4-(tert-butyldimethylsilyloxy)benzylalcohol(27.5 g), N-hydroxyphthalimide (16.8 g) and triphenylphosphine (31.1 g)in tetrahydrofuran (450 ml) at room temperature and stirred for 18hours. After the reaction mixture was concentrated, diisopropyl ether(200 ml) was added and the residual crystals were removed by filtration.The filtrate was concentrated, and the residue was subjected to silicagel chromatography to obtainN-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (17.4 g, yield43%) as crystals from an ethyl acetate-hexane-toluene (1:10:10,v/v)-eluted fraction. The crystals were recrystallized from ethylacetate-hexane to obtain colorless crystals. m.p. 76-77° C.

Reference Example 81

Hydrazine monohydrate (1.25 ml) was added to a solution ofN-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (5.00 g) inethanol (10 ml)-tetrahydrofuran (40 ml) and stirred at 60° C. for 1hour. The reaction mixture was cooled to room temperature, an aqueoussolution of potassium carbonate was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated to obtain4-(tert-butyldimethylsilyloxy)benzyloxyamine (3.15 g, yield 95%) as acolorless oil.

NMR(CDCl₃) δ: 0.19 (6H, s), 0.98 (9H, s), 4.62 (2H, s), 5.20-5.50 (2H,br), 6.83 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.6 Hz).

Reference Example 82

A mixture of 4-(tert-butyldimethylsilyloxy)benzyloxyamine (3.10 g),ethyl 8-oxo-8-phenyloctanoate (6.32 g), acetic acid (2.07 ml), sodiumacetate (1.98 g) and ethanol (80 ml) was heated under reflux for 20hours. The reaction mixture was cooled to room temperature, water wasadded and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was dissolved in tetrahydrofuran(60 ml), tetrabutylammonium fluoride trihydrate (3.98 g) was added andstirred at room temperature for 1 hour. Water was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethylE-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (3.55 g, yield 77%) as acolorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (11H, m), 2.18-2.27 (2H, m), 2.69-2.78 (2H, m),4.12 (2H, q, J=7.1 Hz), 5.13 (2H, s), 5.39 (1H, br s), 6.83 (2H, d,J=8.4 Hz), 7.25-7.38 (5H, m), 7.57-7.63 (2H, m).

Reference Example 83

A mixture of benzonitrile (26.2 g), hydroxylamine hydrochloride (17.7g), potassium carbonate (17.6 g) and 70% ethanol (250 ml) was stirred at80° C. for 2 hours. The reaction mixture was cooled to room temperature,water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas dissolve in acetone (250 ml) and potassium carbonate (19.0 g) wasadded. This mixture was cooled to 0° C. and chloroacetyl chloride (21.9ml) was added dropwise. After stirring for 1 hour, the reaction mixturewas concentrated. Water was added to the residue, the residual crystalswere filtered, washed with water and dissolved in ethyl acetate. Thissolution was washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was dissolved inxylene (250 ml), and refluxed with separating water. After 2 hours, thesolution was concentrated and the remaining crystals were washed withhexane to obtain 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (25.2 g,yield 51%) as pale-yellow crystals. m.p. 38-39° C.

Reference Example 84

A mixture of 4-(tert-butyldimethylsilyloxy)benzyloxyamine (5.31 g),ethyl 6-oxo-6-phenylhexanoate (6.76 g), acetic acid (3.54 ml), sodiumacetate (3.38 g) and ethanol (150 ml) was heated to reflux for 18 hours.The reaction mixture was cooled to room temperature, water was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was dissolved in tetrahydrofuran (100 ml),tetrabutylammonium fluoride trihydrate (10.0 g) was added and stirred atroom temperature for 1 hour. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethyl E-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (5.64 g,yield 77%) as a colorless oil from an ethyl acetate-hexane (2:7,v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.75 (4H, m), 2.23-2.31 (2H,m), 2.73-2.81 (2H, m), 4.09 (2H, q, J=7.1 Hz), 5.04 (1H, s), 5.13 (2H,s), 6.82 (2H, d, J=8.2 Hz), 7.25-7.38 (5H, m), 7.58-7.64 (2H, m).

Reference Example 85

Oxalyl chloride (5.39 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution of 3-benzoylpropionic acid (10.0 g) intetrahydrofuran (100 ml) at room temperature, which was stirred at roomtemperature for 1 hour and concentrated. The residue was dissolved intetrahydrofuran (100 ml) and added dropwise to a 25% aqueous ammonia(100 ml) at 0° C. After stirring at room temperature for 30 minutes,water (1000 ml) and hexane (500 ml) were added, and then the residualcrystals were filtered and washed with hexane to obtain4-oxo-4-butyramide (2.67 g, yield 27%) as orange crystals. m.p. 126-127°C.

Reference Example 86

A solution of 2-[2-(methoxycarbonyl)ethyl]-2-phenyl-1,3-dioxolane (5.00g) in diethyl ether (15 ml) was added dropwise to a mixture of lithiumaluminium hydride (949 mg) and diethyl ether (30 ml) at 0° C. Afterstirring for 30 minutes, water was added to the reaction mixturecarefully and the precipitates were removed by filtration. The filtratewas extracted with ethyl acetate. The ethyl acetate layer was washedwith an aqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain 2-(3-hydroxypropyl)-2-phenyl-1,3-dioxolane (3.81 g, yield 87%) asa colorless oil from an ethyl acetate-hexane (2:3, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.61-1.72 (2H, m), 2.02 (2H, t, J=6.4 Hz), 3.63 (2H, t,J=6.3 Hz), 3.74-3.87(2H, m), 3.95-4.08 (2H, m), 7.24-7.49 (5H, m).

Reference Example 87

To a solution of 2-(3-hydroxypropyl)-2-phenyl-1,3-dioxolane (3.75 g) andtriethylamine (5.05 ml) in ethyl acetate (100 ml) was addedmethanesulfonyl chloride (1.81 ml) at 0° C. After stirring for 30minutes, water was added to the reaction mixture and extracted withethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was dissolved in acetone (100 ml), sodium iodide (5.40 g)was added and stirred at 60° C. for 2 hours. The reaction mixture wasconcentrated, water was added to the residue and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. Theresidual crystals were recrystallized from ethyl acetate-hexane toobtain 2-(3-iodopropyl)-2-phenyl-1,3-dioxolane (5.41 g, yield 94%) ascolorless crystals. m.p. 71-73° C.

Reference Example 88

N-butyllithium (1.6N hexane solution, 2.16 ml) was added dropwise to aolution of diisopropylamine (0.529 ml) in tetrahydrofuran (5 ml) at −20°C. under nitrogen atmosphere. After stirring for 20 minutes, the mixturewas cooled to −78° C., and methyl isobutyrate (0.397 ml) intetrahydrofuran (5 ml) was added dropwise over 30 minutes. The reactionmixture was further stirred for 20 minutes,2-(3-iodopropyl)-2-phenyl-1,3-dioxolane (1.00 g) andhexamethylphosphoramide (0.602 ml) were added. After stirring at −40° C.for 3 hours, dilute hydrochloric acid was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas dissolved in acetone (30 ml), 1N sulfuric acid (10 ml) was added andheated under reflux for 3 hours. The reaction mixture was cooled to roomtemperature, water was added to the reaction mixture and extracted withethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtain methyl2,2-dimethyl-6-oxo-6-phenylhexanoate (350 mg, yield 45%) as a colorlessoil from an ethyl acetate-hexane (1:7, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20 (6H, s), 1.55-1.80 (4H, m), 2.96 (2H, t, J=6.8 Hz),3.65 (3H, s), 7.41-7.61 (3H, m), 7.92-8.02 (2H, m).

Reference Example 89

Sodium borohydride (325 mg) was added to a solution of2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (5.00 g) intetrahydrofuran (30 ml)-methanol (30 ml) at 0° C. After stirring for 1hour, the reaction mixture was poured into water to give crystals.Recrystallization from acetone-ethyl acetate gave2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.17 g, yield83%) as colorless prisms. m.p. 155-156° C.

Reference Example 90

Thionyl chloride (1.69 g) was added dropwise to a stirred suspension of2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.00 g) intoluene (60 ml) at 0° C. After stirring at room temperature for 2 hours,the reaction mixture was concentrated. The residual crystals weredissolved in ethyl acetate and washed with aqueous sodium bicarbonateand water. The ethyl acetate layer was separated, dried (MgSO₄), andconcentrated to give4-(2-cbloromethylphenoxymethyl)-5-methyl-2-phenyloxazole as crystals.Recrystallization from ethyl acetate-hexane gave colorless needles (3.50g, yield 82%). m.p. 103-104° C.

Reference Example 91

Sodium borohydride (540 mg) was added to a solution of3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (10.0g) in tetrahydrofuran (70 ml)-methanol (30 ml) at 0° C. After stirringfor 1 hour, the reaction mixture was poured into water to give3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol(9.25 g, yield 92%) as crystals. Recrystallization from ethylacetate-hexane gave colorless prisms. m.p. 113-114° C.

Reference Example 92

Thionyl chloride (3.62 g) was added dropwise to a stirred suspension of3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol(9.00 g) in tetrahydrofuran (50 ml)-toluene (150 ml) at 0° C. Afterstirring at room temperature for 3 hours, the reaction mixture wasconcentrated. The residual crystals were dissolved in ethyl acetate andwashed with aqueous sodium bicarbonate and water. The ethyl acetatelayer was separated, dried (MgSO₄), and concentrated to give4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazoleas crystals. Recrystallization from acetone-hexane gave colorlessneedles (7.00 g, yield 74%). m.p. 118-119° C.

Reference Example 93

Sodium borohydride (825 mg) was added to a solution of4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzaldehyde (6.84g) in tetrahydrofuran (50 ml)-methanol (50 ml) at 0° C. After stirringfor 1 hour, the reaction mixture was poured into water to give4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl alcohol (6.98g, yield 92%) as crystals.

NMR(CDCl₃) δ: 2.41 (3H, s), 3.88 (3H, s), 4.63 (2H, s), 5.06 (2H, s),6.5-6.55 (1H, m), 6.85-6.95 (1H, m), 6.95-7.05 (3H, m), 7.5-7.55 (1H,m).

Reference Example 94

Thionyl chloride (2.59 g) was added dropwise to a stirred suspension of4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl alcohol (6.30g) in tetrahydrofuran (100 ml) at 0° C. After stirring at roomtemperature for 1 hours, the reaction mixture was poured onto ice togive4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole ascrystals (5.67 g, yield 85%).

NMR(CDCl₃): δ: 2.40 (3H, s), 3.88 (3H, s), 4.56 (2H, s), 5.05 (2H, s),6.5-6.55 (2H, m), 6.9-7.05 (4H, m), 7.5-7.55 (1H, m).

Reference Example 95

In substantially the same manner in Reference Example 93,3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzaldehyde (6.47 g)was reduced by sodium borohydride (760 mg) to obtain3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (6.11 g,yield 93%) as crystals.

NMR(CDCl₃) δ: 2.32 (3H, s), 3.79 (3H, s), 4.54 (2H, s), 4.96 (2H, s),6.7-7.0 (3H, m), 7.3-7.4 (3H, m), 7.9-8.0 (2H, m).

Reference Example 96

In substantially the same manner in Reference Example 94,3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (6.00 g)was reacted with thionyl chloride (1.58 g) to obtain4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (5.77g, yield 91%) as crystals.

NMR(CDCl₃) δ: 2.32 (3H, s), 3.79 (3H, s), 4.47 (2H, s), 4.97 (2H, s),6.7-7.0 (3H, m), 7.3-7.4 (3H, m), 7.9-8.0 (2H, m).

Example 1

To a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol(1.32 g) in toluene (10 ml), thionyl chloride (0.488 ml) was added andthe mixture was stirred for 30 minutes at 60° C. The reaction mixturewas concentrated and the residue was dissolved in N,N-dimethylforrnamide(5 ml), and then added under a nitrogen atmosphere to a mixture ofmethyl Z-2-hydroxyimino-2-phenylacetate (800 mg), sodium hydride (60% inoil, 178 mg) and N,N-dimethylformamide (5 ml) and the mixture wasstirred for 1.5 hours at room temperature. After adding 1N HCl (7 ml)and then aqueous sodium bicarbonate, the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain a colorlessoil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Thisoil was dissolved in methanol (10 ml)-1N aqueous solution of sodiumhydroxide (7 ml) and the mixture was heated under reflux for 1 hour.After adding 1 N HCl (7.5 ml) to the reaction mixture, the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated aqueous sodium chloride, dried (MgSO₄) and then concentrated.The residual crystal was recrystallized from ethyl acetate-hexane toobtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-phenylaceticacid (1.07 g, yield 54%) as colorless crystals. m.p. 171-172° C.(decomposition)

Example 2

To a solution of3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propanol (1.00 g) andtriethylamine (0.866 ml) in ethyl acetate (30 ml), methanesulfonylchloride (0.478 ml) was added dropwise at 0° C., and the mixture wasstirred for 1 hour. The reaction mixture was washed with saturatedaqueous sodium chloride, dried (MgSO₄), and then concentrated. Theresidue was dissolved in N,N-dimethylformamide (10 ml), and methylZ-2-hydroxyimino-2-phenylacetate (830 mg) and sodium hydride (60%, inoil, 185 mg) were added, and the mixture was stirred for 2 hours at roomtemperature. After adding 1N HCl (7 ml) and then aqueous sodiumbicarbonate, the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium chloride, dried(MgSO₄) and then concentrated. The residue was subjected to columnchromatography on silica gel to obtain a colorless oil from a fractioneluted with ethyl acetate-hexane-toluene (1:5:5, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added, and then the mixture wasstirred for 2 hour at 40° C. After adding 1N HCl (5.5 ml) to thereaction mixture, the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainZ-2-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propoxyimino]-2-phenylaceticacid (1.13 g, yield 78%) as colorless crystals. m.p. 165-166° C.(decomposition)

Example 3

To a solution of 4-[2-(methyl-2-pyridylamino)ethoxy]benzylalcohol (1.50g) in toluene (15 ml), thionyl chloride (0.636 ml) was added at 0° C.and the mixture was stirred for 30 minutes. The reaction mixture wasconcentrated and the residue was dissolved in N,N-dimethylformamide (10ml), and then admixed with methyl Z-2-hydroxyimino-2-phenylacetate (1.04g) and sodium hydride (60% in oil, 511 mg) and stirred for 14 hours atroom temperature under nitrogen atmosphere. After adding 1N HCl (20 ml)and then aqueous sodium bicarbonate, the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:2, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (20 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at 40° C. for 1 hour. 1N HCl was added to the reaction mixtureto adjust at pH 4, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate to obtainZ-2-[4-[2-(methyl-2-pyridylamino)ethoxy]benzyloxyimino]-2-phenylaceticacid (959 mg, yield 41%) as colorless crystals. m.p. 93-94° C.

Example 4

To a solution of 4-[2-(methyl-2-pyridylamino)ethoxy]benzylalcohol (1.50g) in toluene (15 ml), thionyl chloride (0.636 ml) was added at 0° C.and the mixture was stirred for 30 minutes. The reaction mixture wasconcentrated and the residue was dissolved in N,N-dimethylformamide (10ml), and then admixed with methyl E-4-hydroxyimino-2-phenylbutyrate(1.20 g) and sodium hydride (60%, in oil, 511 mg) and stirred for 3hours at room temperature under nitrogen atmosphere. After adding 1N HCl(20 ml) and then aqueous sodium bicarbonate, the mixture was extractedwith ethyl acetate. The ethyl acetate-layer was washed with saturatedaqueous sodium chloride, dried (MgSO₄) and then concentrated. Theresidue was subjected to column chromatography on silica gel to obtainan oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Thisoil was dissolved in tetrahydrofuran (20 ml)-methanol (20 ml), and 1Naqueous solution of sodium hydroxide (10 ml) was added and the mixturewas stirred at room temperature for 2 hours. 1N HCl was added to thereaction mixture to adjust at pH 4, and the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated to obtainE-4-[4-[2-(methyl-2-pyridylamino)ethoxy]benzyloxyimino]-2-phenylbutyricacid (1.04 g, yield 41%) as a colorless oil.

NMR(CDCl₃) δ: 2.51-2.62(2H, m), 3.00-3.09(2H, m), 3.13(3H, s), 3.97(2H,t, J=5.6 Hz), 4.19(2H, t, J=5.6 Hz), 5.14(2H, s), 6.50-6.59(2H, m),6.87(2H, d, J=8.8 Hz), 7.24-7.51(6H, m), 7.59-7.65(2H, m), 8.13-8.18(1H,m).

Example 5

Sodium hydride (60%, in oil, 122 mg) was added under a nitrogenatmosphere to a solution of methyl E-2-hydroxyimino-2-phenylacetate (548mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (960mg) in N,N-dimethylformamide (10 ml) at room temperature and the mixturewas stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain a colorlessoil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Thisoil was dissolved in methanol (5 ml)-1N aqueous solution of sodiumhydroxide (5 ml) and the mixture was heated under reflux for 3 hours. 1NHCl (5.5 ml) was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated aqueous sodium chloride, dried (MgSO₄) and then concentrated.The residual crystal was recrystallized from ethyl acetate-isopropylether to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-phenylaceticacid (948 mg, yield 70%) as colorless crystals. m.p. 142-143° C.(decomposition)

Example 6

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethyl E-2-hydroxyimino-3-phenylpropionate(661 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and themixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueoussodium bicarbonate was added, and then the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (4 ml) was added and the mixture wasstirred at room temperature for 1.5 hours. 1N HCl (4.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-isopropyl ether to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionicacid (844 mg, yield 58%) as colorless crystals. m.p. 143-144° C.(decomposition)

Example 7

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of methyl E-4-hydroxyimino-4-phenylbutyrate(661 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and themixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueoussodium bicarbonate was added, and then the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at room temperature for 1.5 hours. 1N HCl (5.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (907 mg, yield 60%) as colorless crystals. m.p. 126-127° C.(decomposition)

Example 8

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethyl E-2-hydroxyiminohexanoate (553 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at room temperature for 30 minutes. 1N HCl (5.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]hexanoic acid(922 mg, yield 68%) as colorless crystals. m.p. 112-114° C.

Example 9

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethyl E-2-hydroxyiminopropionate (418 mg)and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at room temperature for 1 hour. 1N HCl (5.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-isopropylether to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]propionicacid (849 mg, yield 70%) as colorless crystals. m.p. 147-148° C.

Example 10

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethylZ-2-(4-bromophenyl)-2-hydroxyiminoacetate (868 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:2, v/v). This oil wasdissolved in tetrahydrofuran (5 ml)-methanol (10 ml), and 0.5N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture washeated under reflux for 1.5 hours. 1N HCl (5.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate to obtainZ-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (1.34 g, yield 81%) as colorless crystals. m.p. 189-190° C.(decomposition)

Example 11

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethylZ-2-hydroxyimino-2-(4-phenoxylphenyl)acetate (910 mg) and4(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)aceticacid (1.51 g, yield 89%) as colorless crystals. m.p. 184-185° C.(decomposition)

Example 12

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethylE-2-hydroxyimino-2-(4-phenoxylphenyl)acetate (910 mg) and4(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (5.5 ml) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium chloride, dried(MgSO₄) and then concentrated. The residual crystal was recrystallizedfrom ethyl acetate-hexane to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(4-phenoxyphenyl)aceticacid (1.38 g, yield 81%) as colorless crystals. m.p. 152-153° C.(decomposition)

Example 13

Sodium hydride (60% in oil, 107 mg) was added under a nitrogenatmosphere to a solution of methylZ-2-hydroxyimino-2-(3-phenoxylphenyl)acetate (605 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (5.5 ml) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium chloride, dried(MgSO₄) and then concentrated. The residual crystal was recrystallizedfrom ethyl acetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-phenoxyphenyl)aceticacid (738 mg, yield 62%) as colorless crystals. m.p.: 173-174° C.(decomposition)

Example 14

Sodium hydride (60% in oil, 107 mg) was added under a nitrogenatmosphere to a solution of methylE-2-hydroxyimino-2-(3-phenoxylphenyl)acetate (605 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (700 mg) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueoussolution of sodium hydroxide (5 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (5.5 ml) was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated aqueous sodium chloride, dried(MgSO₄) and then concentrated. The residual crystal was recrystallizedfrom ethyl acetate-hexane to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-phenoxyphenyl)aceticacid (745 mg, yield 62%) as a colorless amorphous material. m.p. 55-65°C.

NMR(CDCl₃) δ: 2.45(3H, s), 5.10(2H, s), 5.22(2H, s), 6.98-7.48(16H, m),7.98-8.05(2H, m).

Example 15

Sodium hydride (60% in oil, 209 mg) was added under a nitrogenatmosphere to a solution of ethylZ-2-(4-fluorophenyl)-2-hydroxyiminoacetate (920 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.37 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (7 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate to obtainZ-2-(4-fluorophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (1.66 g, yield 83%) as colorless crystals. m.p. 182-183° C.(decomposition)

Example 16

Sodium hydride (60% in oil, 209 mg) was added under a nitrogenatmosphere to a solution of ethylE-2-(4-fluorophenyl)-2-hydroxyiminoacetate (920 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.37 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (7 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:3, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at 40° C. for 2 hours. 1N HCl (10.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate to obtainE-2-(4-fluorophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (1.08 g, yield 54 to) as colorless crystals. m.p. 150-151° C.(decomposition)

Example 17

Sodium hydride (60% in oil, 153 mg) was added under a nitrogenatmosphere to a solution of ethylE-4-(4-fluorophenyl)-4-hydroxyiminobutyrate (763 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (7 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at room temperature for 1 hour. 1N HCl (7.5 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainE-4-(4-fluorophenyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid (727 mg, yield 47%) as colorless crystals. m.p. 139-140° C.

Example 18

Sodium hydride (60% in oil, 153 mg) was added under a nitrogenatmosphere to a solution of ethyl E-5-hydroxyimino-5-phenylpentanoate(751 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole(1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and themixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueoussodium bicarbonate was added, and then the mixture was extracted withethyl acetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain an oil from afraction eluted with ethyl acetate-hexane (1:4, v/v). This oil wasdissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueoussolution of sodium hydroxide (10 ml) was added and the mixture wasstirred at room temperature for 2 hours. 1N HCl (10.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainE-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-5-phenylpentanoicacid (1.24 g, yield 80%) as colorless crystals. m.p. 129-130° C.

Example 19

Sodium hydride (60% in oil, 127 mg) was added under a nitrogenatmosphere to a solution of ethylZ-2-hydroxyimino-2-(4-methoxyphenyl)acetate (711 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain ethylZ-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetane(1.50 g, yield: 94%) as crystals from a fraction eluted with ethylacetate-hexane (1:2, v/v). Recrystallization was performed from ethylacetate-hexane. m.p. 102-103° C.

Example 20

Sodium hydride (60% in oil, 225 mg) was added under a nitrogenatmosphere to a solution of ethyl 2-hydroxyimino-3-methylbutyrate(Z:E=2.3:1, 1.01 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.00 g) inN,N-dimethylformamide (20 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (10 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain as a firstproduct ethylZ-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(640 mg, yield 23%) as a colorless oil from a fraction eluted with ethylacetate-hexane-dichloromethane (1:10:10, v/v).

NMR(CDCl₃) δ: 1.14(6H, d, J=6.8 Hz), 1.28(3H, t, J=7.1 Hz), 2.43(3H, s),2.70(1H, sept, J=6.8 Hz), 4.29(2H, q, J=7.1 Hz), 4.99(2H, s), 5.03(2H,s), 6.98(2H, d, J=8.8 Hz), 7.27(2H, d, J=8.8 Hz), 7.41-7.49(3H, m),7.97-8.05(2H, m).

Example 21

From a fraction eluted following the Z- form in Example 20, thylE-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(1.34 g, yield 48%) as a colorless oil.

NMR(CDCl₃) δ: 1.17(6H, d, J=7.0 Hz), 1.35(3H, t, J=7.1 Hz), 2.44(3H, s),3.40(1H, sept, J=7.0 Hz), 4.30(2H, q, J=7.1 Hz), 5.00(2H, s), 5.17(2H,s), 7.01(2H, d, J=8.8 Hz), 7.32(2H, d, J=8.8 Hz), 7.40-7.48(3H, m),7.97-8.05(2H, m).

Example 22

Sodium hydride (60% in oil, 225 mg) was added under a nitrogenatmosphere to a solution of ethylE-2-(4-bromophenyl)-2-hydroxyiminoacetate (1.73 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.00 g) inN,N-dimethylformamide (20 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (10 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain ethylE-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(2.54 g, yield 73%) as crystals from a fraction eluted with ethylacetate-hexane (1:3, v/v). Recrystallization was performed from ethylacetate-hexane. m.p. 105-106° C.

Example 23

Sodium hydride (60% in oil, 368 mg) was added under a nitrogenatmosphere to a solution of ethylZ-2-(4-bromophenyl)-2-hydroxyiminoacetate (2.50 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (3.03 g) inN,N-dimethylformamide (25 ml) at room temperature and the mixture wasstirred for 1 hour. After adding 1N HCl (12 ml), aqueous sodiumbicarbonate was added, and then the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residue wassubjected to column chromatography on silica gel to obtain ethylZ-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(3.12 g, yield 61%) as a colorless oil from a fraction eluted with ethylacetate-hexane (1:3, v/v).

NMR(CDCl₃) δ: 1.33(3H, t, J=7.1 Hz), 2.43(3H, s), 4.40(2H, q, J=7.1 Hz),5.00(2H, s), 5.19(2H, s), 7.01(2H, d, J=8.6 Hz), 7.32(2H, d, J=8.6 Hz),7.37-7.54(7H, m), 7.97-8.05(2H, m).

Example 24

EthylZ-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(1.20 g) was dissolved in tetrahydrofuran (5 ml)-methanol (10 ml), and0.5N aqueous solution of sodium hydroxide (10 ml) was added and themixture was heated under reflux for 1 hour. 1N HCl (5.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate to obtainZ-2-(4-methoxyphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (1.02 g, yield 90%) as colorless crystals. m.p. 183-184° C.

Example 25

EthylZ-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(580 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1Naqueous solution of sodium hydroxide (3 ml) was added and the mixturewas stirred for 3 hours at room temperature. 1N HCl (3.3 ml) was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residualcrystals were recrystallized from ethyl acetate-hexane to obtainZ-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid (523 mg, yield 96%) as colorless crystals. m.p. 140-142° C.

Example 26

EthylE-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(1.27 g) was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and1N aqueous solution of sodium hydroxide (5 ml) was added and the mixturewas stirred for 2 hours at room temperature. 1N HCl (5.5 ml) was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with saturated aqueoussodium chloride, dried (MgSO₄) and then concentrated. The residualcrystal was recrystallized from ethyl acetate-hexane to obtainE-3-methyl-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid (1.02 g, yield: 85%) as colorless crystals. m.p. 128-129° C.

Example 27

EthylE-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(600 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1Naqueous solution of sodium hydroxide (3 ml) was added and the mixturewas stirred for 1 hour at 40° C. 1N HCl (3.3 ml) was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theethyl acetate layer was washed with saturated aqueous sodium chloride,dried (MgSO₄) and then concentrated. The residual crystals wererecrystallized from ethyl acetate to obtainE-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (516 mg, yield 99%) as colorless crystals. m.p. 159-160° C.(decomposition)

Example 28

A mixture of ethylE-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(800 mg), phenylboronic acid (213 mg), potassium carbonate (604 mg),toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under anargon atmosphere for 30 minutes at room temperature. Tetrakis(triphenylphosphine)palladium (0) (101 mg) was added and the mixture washeated under reflux for 15 hours. The reaction mixture was washed withsaturated aqueous sodium chloride, dried (MgSO₄) and then concentrated.The residue was subjected to column chromatography on silica gel toobtain an oil from a fraction eluted with ethyl acetate-hexane (1:3,v/v). This oil was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml),and 1N aqueous solution of sodium hydroxide (3 ml) was added and themixture was stirred for 2 hours at 40° C. 1N HCl (3.3 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainE-2-(4-biphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (642 mg, yield 85%) as colorless crystals. m.p. 148-149° C.(decomposition)

Example 29

A mixture of ethylZ-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(1.43 g), phenylboronic acid (476 mg), potassium carbonate (1.44 g),toluene (30 ml), ethanol (3 ml) and water (3 ml) was stirred under anargon atmosphere for 30 minutes at room temperature. Tetrakis(triphenylphosphine)palladium (0) (180 mg) was added and the mixture washeated under reflux for 13 hours. The reaction mixture was washed withsaturated aqueous sodium chloride, dried (MgSO₄) and then concentrated.The residue was subjected to column chromatography on silica gel toobtain an oil from a fraction eluted with ethylacetate-hexane-dichloromethane (1:10:10, v/v). This oil was dissolved intetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution ofsodium hydroxide (5 ml) was added and the mixture was stirred for 2hours at 40° C. 1N HCl (5.5 ml) was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The ethyl acetate layerwas washed with saturated aqueous sodium chloride, dried (MgSO₄) andthen concentrated. The residual crystal was recrystallized from ethylacetate-isopropylether to obtainZ-2-(4-biphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (807 mg, yield 60%) as colorless crystals. m.p. 193-194° C.(decomposition)

Example 30

A mixture of ethylZ-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(800 mg), 3-thienylboronic acid (224 mg), potassium carbonate (604 mg),toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred under anargon atmosphere for 30 minutes at room temperature. Tetrakis(triphenylphosphine)palladium (0) (101 mg) was added and the mixture washeated under reflux for 14 hours. The reaction mixture was washed withsaturated aqueous sodium chloride, dried (MgSO₄) and then concentrated.The residue was subjected to column chromatography on silica gel toobtain an oil from a fraction eluted with ethyl acetate-hexane (1:3,v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml),and 1N aqueous solution of sodium hydroxide (5 ml) was added and themixture was stirred for 2 hours at 40° C. 1N HCl (5.5 ml) was added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The ethyl acetate layer was washed with saturated aqueous sodiumchloride, dried (MgSO₄) and then concentrated. The residual crystal wasrecrystallized from ethyl acetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4-(3-thienyl)phenyl]aceticacid (442 mg, yield 58%) as pale-yellow crystals. m.p. 205-206° C.(decomposition)

Example 31

A mixture of ethylZ-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(830 mg), 4-(E-2-phenylethenyl)phenylboronic acid (268 mg), potassiumcarbonate (626 mg), toluene (20 ml), ethanol (2 ml) and water (2 ml) wasstirred under an argon atmosphere for 30 minutes at room temperature.Tetrakis (triphenylphosphine)palladium (0) (105 mg) was added and themixture was heated under reflux for 14 hours. The reaction mixture waswashed with saturated aqueous sodium chloride, dried (MgSO₄) and thenconcentrated. The residues were subjected to column chromatography onsilica gel to obtain an oil from a fraction eluted with ethylacetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml)was added and the mixture was stirred for 2 hours at 40° C. 1N HCl (5.5ml) was added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedaqueous sodium chloride, dried (MgSO₄) and then concentrated. Theresidual crystal was recrystallized from ethyl acetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[4-(E-2-phenylethenyl)phenyl]aceticacid (634 mg, yield: 77%) as pale-yellow crystals. m.p. 194-195° C.(decomposition)

Example 32

Sodium hydride (60% in oil, 153 mg) was added to a solution of ethylZ-2-hydroxyimino-2-(3-pyridyl)acetate (619 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature under nitrogenatmosphere and stirred for 3 hours. 1N hydrochloric acid (7 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate(1.12 g, yield 74%) as a pale-yellow oil from an ethyl acetate-hexane(1:1, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 2.44 (3H, s), 4.42 (2H, q, J=7.1Hz), 5.00 (2H, s), 5.22 (2H, s), 7.01 (2H, d, J=8.8 Hz), 7.25-7.37 (3H,m), 7.40-7.48 (3H, m), 7.86-7.93 (1H, m), 7.99-8.05 (2H, m), 8.61-8.65(1H, m), 8.75-8.78 (1H, m).

Example 33

Sodium hydride (60%, in oil, 153 mg) was added to a solution of ethylE-2-hydroxyimino-2-(3-pyridyl)acetate (619 mg) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature under nitrogenatmosphere and stirred for 3 hours. 1N hydrochloric acid (7 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate(1.02 g, yield 68%) as a pale-yellow oil from an ethyl acetate-hexane(1:1, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.36 (3H, t, J=7.1 Hz), 2.44 (3H, s), 4.37 (2H, q, J=7.1Hz), 4.99 (2H, s), 5.27 (2H, s), 7.00 (2H, d, J=8.8 Hz), 7.25-7.38 (3H,m), 7.41-7.48 (3H, m), 7.72-7.80 (1H, m), 7.98-8.05 (2H, m), 8.57-8.62(1H, m), 8.66-8.70 (1H, m).

Example 34

m-Chloroperoxybenzoic acid (70%, 282 mg) was added to a solution ofethyl-Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3pyridyl)acetate(450 mg) in tetrahydrofuran (10 ml) at room temperature and stirred for17 hours. An aqueous saturated solution of sodium thiosulfate (10 ml)and an aqueous saturated solution of potassium carbonate (10 ml) wereadded and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain an oil from an ethyl acetate-methanol (10:1,v/v)-eluted fraction. This was dissolved in tetrahydrofuran (10ml)-methanol (5 ml), 1N an aqueous saturated solution of sodiumhydroxide (5 ml) was added and stirred at 40° C. for 2 hours. 1Nhydrochloric acid (5.5 ml) was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was recrystallized from acetone-diisopropylether to obtainZ-2-[4-(5-methyl-2-phenyl--4-oxazolylmethoxy)benzyloxyimino]-2-(pyridine-1-oxide-3-yl)aceticacid (282 mg, yield 64%) as colorless crystals. m.p. 181-182° C.(decomposition)

Example 35

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate(520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40°C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized from ethylacetate to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)aceticacid (321 mg, yield 66%) as colorless crystals. m.p. 156-157° C.(decomposition)

Example 36

m-Chloroperoxybenzoic acid (70%, 282 mg) was added to a solution ofethylE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate(450 mg) in tetrahydrofuran (10 ml) at room temperature and stirred for17 hours. An aqueous saturated solution of sodium thiosulfate (10 ml)and an aqueous saturated solution of potassium carbonate (10 ml) wereadded and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain an oil from an ethyl acetate-methanol (10:1,v/v)-eluted fraction. This was dissolved in tetrahydrofuran (10ml)-methanol (5 ml), a 1N aqueous saturated solution of sodium hydroxide(5 ml) was added and stirred at 40° C. for 2 hours. 1N hydrochloric acid(5.5 ml) was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas recrystallized from ethyl acetate-hexane to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(pyridine-1-oxide-3-yl)aceticacid (228 mg, yield 52%) as colorless crystals. m.p. 161-162° C.(decomposition)

Example 37

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate(520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40°C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized fromacetone-diisopropyl ether to obtainE-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)aceticacid (427 mg, yield 88%) as colorless crystals. m.p. 130-131° C.(decomposition)

Example 38

Sodium hydride (60%, in oil, 203 mg) was added to a solution of ethylZ-2-(3-bromophenyl)-2-hydroxyiminoacetate (1.15 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.33 g) inN,N-dimethylformamide (15 ml) at room temperature under nitrogenatmosphere and stirred for 1 hour. 1N hydrochloric acid (7 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylZ-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(1.12 g, yield 48%) as a pale-yellow oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.33 (3H, t, J=7.1 Hz), 2.44 (3H, s), 4.41 (2H, q, J=7.1Hz), 5.00 (2H, s), 5.20 (2H, s), 7.01 (2H, d, J=8.8 Hz), 7.20-7.56 (8H,m), 7.73-7.76 (1H, m), 7.99-8.06 (2H, m).

Example 39

Sodium hydride (60% in oil, 399 mg) was added to a solution of ethylZ-2-(3-benzoylphenyl)-2-hydroxyiminoacetate (2.47 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.61 g) inN,N-dimethylformamide (15 ml) at room temperature under nitrogenatmosphere and stirred for 1 hour. 1N hydrochloric acid (15 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylZ-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(1.97 g, yield 41%) as a pale-yellow oil from an ethyl acetate-hexane(1:3, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.31 (3H, t, J=7.1 Hz), 2.43 (3H, s), 4.40 (2H, q, J=7.1Hz), 4.99 (2H, s), 5.20 (2H, s), 7.00 (2H, d, J=8.8 Hz), 7.25-7.72 (11H,m), 7.76-7.86 (3H, m), 7.96-8.05 (2H, m).

Example 40

A 1N aqueous saturated solution of sodium hydroxide (7 ml) was added toa solution of ethylZ-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(800 mg) in tetrahydrofuran (14 ml)-methanol (7 ml) and stirred at 40°C. for 1 hour. 1N hydrochloric acid (7.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized from ethylacetate-hexane to obtainZ-2(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]aceticacid (608 mg, yield 80%) as orange crystals. m.p. 185-186° C.(decomposition)

Example 41

Potassium tert-butoxide (328 mg) was added to a mixture ofmethyltriphenylphosphonium bromide (1.14 g) and tetrahydrofuran (10 ml)under nitrogen atmosphere and stirred at room temperature for 1 hour. Asolution of ethylZ-2-(3-benzoylphenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(1.12 g) in tetrahydrofuran (10 ml) was added dropwise, stirred furtherfor 3 hours, dilute hydrochloric acid was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetate(880 mg, yield 79%) as a pale brown oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 2.43 (3H, s), 4.36 (2H, q, J=7.1Hz), 4.99 (2H, s), 5.18 (2H, s), 5.48 (2H, d, J=6.4 Hz), 6.99 (2H, d,J=8.6 Hz), 7.25-7.55 (14H, m), 7.99-8.05 (2H, m).

Example 42

A mixture of ethylZ-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(780 mg), E-styrylboronic acid (252 mg), potassium carbonate (589 mg),toluene (20 ml), water (2 ml) and ethanol (2 ml) was stirred at roomtemperature for 30 minutes under argon atmosphere. To this was addedtetrakis(triphenylphosphine)palladium (0) (98 mg) and heated to refluxfor 15 hours. After the reaction mixture was cooled to room temperature,the organic layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(E-3-styryl)acetate(610 mg, yield 75%) as pale brown oil from an ethyl acetate-hexane (1:4,v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.35 (3H, t, J=7.1 Hz), 2.43 (3H, s), 4.43 (2H, q, J=7.1Hz), 5.00 (2H, s), 5.23 (2H, s), 7.01 (2H, d, J=8.4 Hz), 7.11 (2H, s),7.25-7.60 (13H, m), 7.69 (1H, br s), 7.99-8.05 (2H, m).

Example 43

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylZ-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate(430 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40°C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized from ethylacetate-hexane to obtainZ-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxyimino]aceticacid (370 mg, yield 91%) as colorless crystals. m.p. 181-182° C.(decomposition)

Example 44

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]acetate(780 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40°C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized from ethylacetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-[3-(1-phenylvinyl)phenyl]aceticacid (701 mg, yield 95%) as colorless crystals. m.p. 171-172° C.

Example 45

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(E-3-styryl)acetate(500 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40°C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reactionmixture and extracted with ethyl acetate. The ethyl acetate layer waswashed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was recrystallized from ethylacetate-hexane to obtainZ-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(E-3-styryl)aceticacid (474 mg, yield 95%) as colorless crystals. m.p. 178-179° C.

Example 46

Sodium hydride (60% in oil, 211 mg) was added to a solution of ethylE-4-(hydroxyimino)-4-(4-phenoxyphenyl)butyrate(1.50 g) and4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.50 g) inN,N-dimethylformamide (15 ml) at room temperature under nitrogenatmosphere and stirred for 1 hour. 1N hydrochloric acid (7 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain crystals from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.The crystals were recrystallized from ethyl acetate-hexane to obtainethylE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyrate(1.87 g, yield 66%) as colorless crystals. m.p. 118-119° C.

Example 47

A 1N aqueous saturated solution of sodium hydroxide (10 ml) was added toa solution of ethylE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyrate(1.60g) in tetrahydrofuran (20 ml)-methanol (10 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (10.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-phenoxyphenyl)butyicacid (1.50 g, yield 99%) as colorless crystals. m.p. 131-132° C.

Example 48

Sodium hydride (60% in oil, 134 mg) was added to a solution of methylE-4-(hydroxyimino)-4-phenylbutyrate (632 mg) and4-[2-(4-chloromethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (1.00 g) inN,N-dimethylformamide (10 ml) at room temperature under nitrogenatmosphere and stirred for 1 hour. 1N hydrochloric acid (5 ml) wasadded, an aqueous saturated solution of sodium bicarbonate was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain crystals from an ethyl acetate-hexane (1:3, v/v)-eluted fraction.The crystals were recrystallized from ethyl acetate-hexane to obtainmethylE-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyrate(650 mg, yield 43%) as colorless crystals. m.p. 73-74° C.

Example 49

Thionyl chloride (0.633 ml) was added dropwise to a solution of4-[2-(methyl-2-pyrimidylamino)ethoxy]benzylalcohol (1.50 g) in toluene(25 ml) at 0° C., which was stirred for 30 minutes and concentrated. Theresidue was dissolved in N,N-dimethylformamide (10 ml), methylE-4-(hydroxyimino)-4-phenylbutyrate (1.20 g) was added, sodium hydride(60% in oil, 509 mg) was further added at room temperature undernitrogen atmosphere and stirred for 1 hour. 1N hydrochloric acid (20 ml)was added to the reaction mixture, an aqueous saturated solution ofsodium bicarbonate and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain methylE-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyrate(1.32 g, yield 51%) as a dark red oil from an ethyl acetate-hexane (1:2,v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.49-2.58 (2H, m), 3.00-3.09 (2H, m), 3.30 (3H, s), 3.62(3H, s), 4.02 (2H, t, J=5.7 Hz), 4.21 (2H, t, J=5.7 Hz), 5.14 (2H, s),6.48 (1H, t, J=4.8 Hz), 6.90 (2H, d, J=8.4 Hz), 7.29-7.38 (5H, m),7.59-7.65 (2H, m), 8.31 (2H, d, J=4.8 Hz).

Example 50

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of methylE-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyrate(460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyricacid (443 mg, yield 99%) as colorless crystals. m.p. 106-107° C.

Example 51

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of methylE-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyrate(1.22 g) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-[2-(methyl-2-pyrimidylamino)ethoxy]benzyloxyimino]-4-phenylbutyricacid (1.09 g, yield 92%) as colorless crystals. m.p. 72-73° C.

Example 52

A mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (1.00g), ethyl benzoylacetate (0.612 ml), acetic acid (0.554 ml), sodiumacetate (528 mg) and ethanol (20 ml) was heated to reflux for 12 hoursand cooled to room temperature. Water was added to the reaction mixtureand extracted with ethyl acetate. The ethyl acetate layer was washedwith an aqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate(1.29 g, yield 83%) as a colorless oil from an ethyl acetate-hexane(1:3, v/v).

NMR(CDCl₃) δ: 1.15 (3H, t, J=7.1 Hz), 2.44 (3H, s), 3.76 (2H, s), 4.09(2H, q, J=7.1 Hz), 5.00 (2H, s), 5.20 (2H, s), 7.01 (2H, d, J=8.4 Hz),7.30-7.50 (8H, m), 7.61-7.67 (2H, m), 7.97-8.05 (2H, m).

Example 53

Lithium hydroxide monohydrate (402 mg) was added to a solution of ethylE-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate(1.16 g) in tetrahydrofuran (60 ml)-water (40 ml) and stirred at roomtemperature for 18 hours. Dilute hydrochloric acid was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized to obtain3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionicacid (1.08 g, yield 99%) as colorless crystals. m.p. 107-108° C.

Example 54

Sodium hydride (60%, in oil, 143 mg) was added to a solution of methylE-4-(hydroxyimino)-4-phenylbutyrate (676 mg) and5-chloro-2-(4-chloromethylphenoxymethyl)imidazo[1,2-a]pyridine (1.00 g)in N,N-dimethyformamide (10 ml) at room temperature and stirred for 1hour. 1N hydrochloric acid (7 ml) was added, an aqueous saturatedsolution of sodium bicarbonate was added and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain methylE-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.04 g, yield 67%) as a colorless oil from an ethyl acetate-hexane(2:1, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.60 (2H, m), 3.01-3.11 (2H, m), 3.62 (3H, s), 5.17(2H, s), 5.31 (2H, s), 6.90 (1H, d, J=7.4 Hz), 7.04 (2H, d, J=8.6 Hz),7.19 (1H, dd, J=7.4, 8.8 Hz), 7.30-7.39 (5H, m), 7.55-7.66 (3H, m), 7.85(1H, s).

Example 55

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of methylE-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(400 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyricacid (313 mg, yield 78%) as colorless crystals. m.p. 160-161° C.

Example 56

A mixture of methylE-4-[4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(550 mg), phenylboronic acid (168 mg), sodium bicarbonate (348 mg),toluene (20 ml), water (2 ml) and methanol (2 ml) was stirred at roomtemperature for 30 minutes under argon atmosphere. To this was addedtetrakis(triphenylphosphine)palladium (0) (80 mg) and heated to refluxfor 36 hours. The reaction mixture was cooled to room temperature, theorganic layer was washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was subjected tosilica gel chromatography to obtain methylE-4-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(490 mg, yield 82%) as a colorless oil from an ethyl acetate-hexane(3:2, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.49-2.58 (2H, m), 3.00-3.10 (2H, m), 3.61 (3H, s), 5.15(2H, s), 5.24 (2H, s), 6.75 (1H, d, J=7.0 Hz), 7.01 (2H, d, J=8.8 Hz),7.24-7.37 (6H, m), 7.51-7.63 (8H, m), 7.72 (1H, s).

Example 57

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of methylE-4-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(400 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-phenylimidazo[1,2-alpyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyricacid (365 mg, yield 94%) as colorless crystals. m.p. 160-161° C.

Example 58

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), ethyl 6-oxo-6-phenylhexanoate (415 mg), acetic acid (0.276ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to refluxfor 13 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(620 mg, yield 73%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.73 (4H, m), 2.28 (2H, t,J=7.3 Hz), 2.44 (3H, s), 2.78 (2H, t, J=7.5 Hz), 4.09 (2H, q, J=7.1 Hz),5.00 (2H, s), 5.15 (2H, s), 7.01 (2H, d, J=8.4 Hz), 7.33-7.48 (8H, m),7.58-7.64 (2H, m), 7.99-8.05 (2H, m).

Example 59

EthylZ-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(120 mg, yield 14%) was obtained as a colorless oil from a fractionwhich eluted following the E- compound in Example 58.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.38-1.71 (4H, m), 2.26 (2H, t,J=7.3 Hz), 2.43 (3H, s), 2.53 (2H, t, J=7.5 Hz), 4.09 (2H, q, J=7.1 Hz),4.99 (2H, s), 5.02 (2H, s), 6.97 (2H, d, J=8.4 Hz), 7.23-7.47 (10H, m),7.97-8.05 (2H, m).

Example 60

A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added toa solution of ethylE-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(530 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-6-[4-(5-methyl-2-pheny]-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoicacid (451 mg, yield 90%) as colorless crystals. m.p. 112-113° C.

Example 61

A 1N aqueous saturated solution of sodium hydroxide (3 ml) was added toa solution of ethylZ-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(120 mg) in tetrahydrofuran (6 ml)-methanol (3 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (3.3 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainZ-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoicacid (113 mg, yield 99%) as colorless crystals. m.p. 101-102° C.

Example 62

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), 3-oxo-1-indancarboxylic acid (284 mg), acetic acid (0.276 ml),sodium acetate (264 mg) and ethanol (20 ml) was heated to reflux for 18hours, the mixture was cooled to room temperature. Water was added tothe reaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-1-indancarboxylicacid (522 mg, yield 69%) as colorless crystals. m.p. 148-149° C.

Example 63

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), ethyl 4-oxo-4-(2-pyridyl)butyrate (367 mg), acetic acid (0.276ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to refluxfor 20 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyrate(600 mg, yield 75%) as a colorless oil from an ethyl acetate-hexane(2:7, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.23 (3H, t, J=7.1 Hz), 2.44 (3H, s), 2.55-2.64 (2H, m),3.19-3.28 (2H, m), 4.07 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.19 (2H, s),7.01 (2H, d, J=8.8 Hz), 7.19-7.24 (1H, m), 7.36 (2H, d, J=8.8 Hz),7.39-7.46 (3H, m), 7.64 (1H, dt, J=1.8, 7.6 Hz), 7.87 (1H, d, J=8.0 Hz),7.99-8.05 (2H, m), 8.54-8.59 (1H, m).

Example 64

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyrate(520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(2-pyridyl)butyricacid (425 mg, yield 87%) as colorless crystals. m.p. 116-117° C.

Example 65

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), ethyl 4-(2-furyl)-4-oxobutyrate (347 mg), acetic acid (0.276ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to refluxfor 96 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(190 mg, yield 24%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.25 (3H, t, J=7.1 Hz), 2.44 (3H, s), 2.62-2.71 (2H, m),2.95-3.04 (2H, m), 4.13 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.14 (2H, s),6.45-6.49 (1H, m), 7.01 (2H, d, J=8.8 Hz), 7.25-7.28 (1H, m), 7.34 (2H,d, J=8.8 Hz), 7.39-7.48 (4H, m), 7.99-8.05 (2H, m).

Example 66

EthylZ-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(510 mg, yield 65%) was obtained as a colorless oil from a fractionwhich eluted following the E-compound in Example 65.

NMR(CDCl₃) δ: 1.21 (3H, t, J=7.1 Hz), 2.43 (3H, s), 2.53-2.62 (2H, m),2.89-2.98 (2H, m), 4.09 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.17 (2H, s),6.43 (1H, dd, J=1.8, 3.2 Hz), 6.68 (1H, d, J=1.8 Hz), 7.01 (2H, d, J=8.8Hz), 7.34 (2H, d, J=8.8 Hz), 7.38-7.47 (4H, m), 7.97-8.05 (2H, m).

Example 67

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), ethyl 4-oxo-4-(3-pyridyl)butyrate (367 mg), acetic acid (0.276ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to refluxfor 20 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethyl4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyrate(590 mg, yield 73%) as a colorless oil from an ethyl acetate-hexane(3:2, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.16-1.30 (3H, m), 2.44 (3H, s), 2.51-2.64 (2H, m), 2.86(0.4H, t, J=6.9 Hz), 3.05 (1.6H, t, J=7.9 Hz), 4.02-4.18 (2H, m), 5.00(2.4H, s like), 5.18 (1.6H, s), 6.95-7.06 (2H, m), 7.23-7.48 (6H, m),7.71-7.78 (0.2H, m), 7.91-8.05 (2.8H, m), 8.53-8.61 (1H, m), 8.66-8.69(0.2H, m), 8.85-8.88 (0.8H, m).

Example 68

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylZ-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainZ-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid (402 mg, yield 93%) as colorless crystals. m.p. 131-133° C.

Example 69

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), ethyl 4-oxo-4-(4-pyridyl)butyrate (367 mg), acetic acid (0.276ml), sodium acetate (264 mg) and ethanol (20 ml) was heated to refluxfor 15 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethyl4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyrate(740 mg, yield 92%) as a colorless oil from an ethyl acetate-hexane(3:2, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.16-1.31 (3H, m), 2.44 (3H, s), 2.48-4.63 (2H, m),2.77-2.86 (0.5H, m), 3.02 (1.5H, t, J=7.9 Hz), 4.02-4.18 (2H, m), 5.00(2.5H, s like), 5.20 (1.5H, s), 6.95-7.22 (2H, m), 7.20-7.56 (7H, m),7.99-8.05 (2H, m), 8.59-8.66 (2H, m).

Example 70

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethyl4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyrate(520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(3-pyridyl)butyricacid (378 mg, yield 77%) as colorless crystals. m.p. 158-159° C.

Example 71

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethyl4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyrate(670 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-(4-pyridyl)butyricacid (475 mg, yield 75%) as colorless crystals. m.p. 161-162° C.

Example 72

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate(190 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyricacid (140 mg, yield 78%) as colorless crystals. m.p. 124-125° C.

Example 73

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(500 mg), methyl 9-oxo-9-phenylnonanoate (464 mg), 1N hydrochloric acid(3 ml), sodium acetate (264 mg) and methanol (20 ml) was heated toreflux for 72 hours, the mixture was cooled to room temperature. Waterwas added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain an oil from an ethylacetate-hexane (1:6, v/v)-eluted fraction. This was dissolved intetrahydrofuran (10 ml)-methanol (5 ml), a 1N aqueous saturated solutionof sodium hydroxide (5 ml) was added and stirred at room temperature for1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixtureand extracted with ethyl acetate. The ethyl acetate layer was washedwith an aqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was recrystallized from ethyl acetate-hexaneto obtainE-9-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-9-phenylnonanoicacid (323 mg, yield 37%) as colorless crystals. m.p. 67-68° C.

Example 74

After a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), methyl 4-oxo-4-phenylbutyrate (371 mg), acetic acid (0.331ml), sodium acetate (317 mg) and methanol (20 ml) was heated to refluxfor 40 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain methylE-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(570 mg, yield 61%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.43 (3H, s), 2.53-2.62 (2H, m), 3.04-3.13 (2H, m), 3.62(3H, s), 5.01 (2H, s), 5.22 (2H, s), 6.94-7.08 (3H, m), 7.28-7.48 (7H,m), 7.60-7.66 (2H, m), 7.97-8.05 (2H, m).

Example 75

After a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), ethyl 6-oxo-6-phenylhexanoate (452 mg), acetic acid (0.331ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to refluxfor 15 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(590 mg, yield 58%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.21 (3H, t, J=7.1 Hz), 1.47-1.80 (4H, m), 2.29 (2H, t,J=7.5 Hz), 2.43 (3H, s), 2.80 (2H, t, J=7.5 Hz), 4.08 (2H, q, J=7.1 Hz),5.01 (2H, s), 5.20 (2H, s), 6.93-7.08 (3H, m), 7.25-7.47 (7H, m),7.58-7.64 (2H, m), 7.97-8.05 (2H, m).

Example 76

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-6-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoicacid (432 mg, yield 88%) as colorless crystals. m.p. 114-115° C.

Example 77

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of methylE-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(500 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room.temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (395 mg, yield 82%) as colorless crystals. m.p. 108-109° C.

Example 78

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), ethyl 7-oxo-7-phenylheptanoate (959 mg), acetic acid (0.331ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to refluxfor 18 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoate(800 mg, yield 72%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.08-1.70 (9H, m), 2.24 (2H, t, J=7.5 Hz), 2.44 (3H, s),2.76 (2H, t, J=7.5 Hz), 4.11 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.15 (2H,s), 7.02 (2H, d, J=8.8 Hz), 7.33-7.48 (8H, m), 7.57-7.63 (2H, m),7.99-8.05 (2H, m).

Example 79

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(1.50 g), ethyl 8-oxo-8-phenyloctanoate (2.54 g), acetic acid (0.830ml), sodium acetate (793 mg) and ethanol (40 ml) was heated to refluxfor 18 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylE-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate(2.02 g, yield 76%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.18-1.65 (11H, m), 2.25 (2H, t, J=7.5 Hz), 2.44 (3H, s),2.75 (2H, t, J=7.5 Hz), 4.12 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.15 (2H,s), 7.01 (2H, d, J=8.8 Hz), 7.33-7.46 (8H, m), 7.58-7.64 (2H, m),7.99-8.05 (2H, m).

Example 80

EthylZ-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate(408 mg, yield 15%) was obtained as a colorless oil from a fractionwhich eluted following the E-compound in Example 79.

NMR(CDCl₃) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J=7.5 Hz), 2.43 (3H, s),2.50 (2H, t, J=7.2 Hz), 4.12 (2H, q, J=7.1 Hz), 4.99 (2H, s), 5.02 (2H,s), 6.97 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz), 7.27-7.48 (8H, m),7.99-8.04 (2H, m).

Example 81

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate(660 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoicacid (580 mg, yield 92%) as colorless crystals. m.p. 116-117° C.

Example 82

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), 6-oxo-6-phenylhexanamide (396 mg), acetic acid (0.331 ml),sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 18hours, the mixture was cooled to room temperature. Water was added tothe reaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain crystals from an ethyl acetate-hexane (3:1,v/v)-eluted fraction. The crystals were recrystallized from ethylacetate-hexane to obtainE-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanamide(651 mg, yield 68%) as colorless crystals. m.p. 95-96° C.

Example 83

A mixture of 4-(chloromethyl)-2-(2-furyl)-5-methyloxazole (340 g), ethylE-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg), potassiumcarbonate (432 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate(717 mg, yield 84%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J=7.5 Hz), 2.42 (3H, s),2.70-2.79 (2H, m), 4.11 (2H, q, J=7.1 Hz), 5.00 (2H, s), 5.15 (2H, s),6.51-6.54 (1H, m), 6.96-7.03 (3H, m), 7.31-7.40 (5H, m), 7.53-7.56 (1H,m), 7.58-7.64 (2H, m).

Example 84

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(1.00 g), methyl 4-oxo-4-phenylbutyrate (619 mg), acetic acid (0.553ml), sodium acetate (528 mg) and methanol (20 ml) was heated to refluxfor 19 hours, the mixture was cooled to room temperature. Water wasadded to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain methylE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.18 g, yield 76%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.44 (3H, s), 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62(3H, s), 5.01 (2H, s), 5.17 (2H, s), 7.01 (2H, d, J=8.8 Hz), 7.33-7.48(8H, m), 7.60-7.66 (2H, m), 7.99-8.06 (2H, m).

Example 85

MethylZ-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(222 mg, yield 14%) was obtained as a colorless oil from a fractionwhich eluted following the E-compound in Example 84.

NMR(CDCl₃) δ: 2.43 (3H, s), 2.57 (2H, t, J=7.0 Hz), 2.84 (2H, t, J=7.0Hz), 3.62 (3H, s), 5.00 (4H, s like), 6.98 (2H, d, J=8.8 Hz), 7.26 (2H,d, J=8.8 Hz), 7.30-7.48 (8H, m), 7.99-8.05 (2H, m).

Example 86

A mixture of 5-(chloromethyl)-3-phenylisoxazole (238 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (350 mg), potassiumcarbonate (310 mg) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 13 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyrate(358 mg, yield 62%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.17(2H, s), 5.22 (2H, s), 6.66 (1H, s), 6.99 (2H, d, J=8.8 Hz), 7.34-7.49(8H, m), 7.59-7.65 (2H, m), 7.78-7.84 (2H, m).

Example 87

Lithium hydroxide monohydrate (58.3 mg) was added to a solution ofmethylE-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyrate(326 mg) in tetrahydrofuran (6 ml)-water (4 ml) and stirred at roomtemperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyricacid (306 mg, yield 97%) as colorless crystals. m.p. 96-97° C.

Example 88

A mixture of 3-(chloromethyl)-5-phenylisoxazole (340 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassiumcarbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 72 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyrate(472 mg, yield 63%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.59 (2H, m), 3.01-3.11 (2H, m), 3.62 (3H, s), 5.16(2H, s), 5.21 (2H, s), 6.66 (1H, s), 7.01 (2H, d, J=8.8 Hz), 7.34-7.53(8H, m), 7.57-7.65 (2H, m), 7.74-7.82 (2H, m).

Example 89

A mixture of 4-(chloromethyl)-5-methyl-2-phenylthiazol (394 mg), methyE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassiumcarbonate (442 mg) and N,N-dimethyformamide (10 ml) was stirred at roomtemperature for 72 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was subjected tosilica gel chromatography to obtain methyE-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(570 mg, yield 71%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.60 (5H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.17(2H, s), 5.18 (2H, s), 7.04 (2H, d, J=8.6 Hz), 7.33-7.51 (8H, m),7.58-7.66 (2H, m), 7.85-7.93 (2H, m).

Example 90

Lithium hydroxide monohydrate (73.5 mg) was added to a solution ofmethylE-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyrate(412 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-4-phenyl-4-[4-(5-phenyl-3-isoxazolylmethoxy)benzyloxyimino]butyricacid (320 mg, yield 80%) as colorless crystals. m.p. 100-101° C.

Example 91

Lithium hydroxide monohydrate (83.6 mg) was added to a solution ofmethylE-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(500 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (8 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (2.1 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (363 mg, yield 75%) as colorless crystals. m.p. 99-100° C.

Example 92

A mixture of 4-(chloromethyl)-2-(2-furyl)-5-methyloxazole (348 mg),methyl E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg),potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) wasstirred at room temperature for 18 hours. Water was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain methylE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate(507 mg, yield 67%) as a colorless oil from an ethyl acetate-hexane(1:3, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.42 (3H, s), 2.50-2.59 (2H, m), 3.01-3.11 (2H, m), 3.62(3H, s), 5.00 (2H, s), 5.16 (2H, s), 6.51-6.54 (1H, m), 6.95-7.02 (3H,m), 7.28-7.40 (5H, m), 7.52-7.55 (1H, m), 7.59-7.66 (2H, m).

Example 93

A mixture of 4-(chloromethyl)-5-methyl-2-(2-thienyl)oxazole (376 mg),methyl E-4-[(4-hydroxybenzyloxy)imino]-4-phenylbutyrate (500 mg),potassium carbonate (442 mg) and N,N-dimethylformamide (10 ml) wasstirred at room temperature for 40 hours. Water was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain methylE-4-[4-[5-methyl-2-(2-thenyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate(495 mg, yield 63%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.41 (3H, s), 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.63(3H, s), 4.98 (2H, s), 5.16 (2H, s), 6.99 (2H, d, J=8.8 Hz), 7.10 (1H,dd, J=3.6, 5.0 Hz), 7.32-7.42 (6H, m), 7.59-7.66 (3H, m).

Example 94

Lithium hydroxide monohydrate (76.0 mg) was added to a solution ofmethylE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate(430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (1.9 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyricacid (328 mg, yield 79%) as colorless crystals. m.p. 124-125° C.

Example 95

A mixture of 4-(chloromethyl)-5-methyl-2-(2-thienyl)oxazole (368 mg),ethyl E-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg),potassium carbonate (432 mg) and N,N-dimethylformamide (7 ml) wasstirred at room temperature for 18 hours. Water was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain ethylE-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate(762 mg, yield 95%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (11H, m), 2.25 (2H, t, J=7.3 Hz), 2.41 (3H, s),2.70-2.79 (2H, m), 4.11 (2H, q, J=7.1 Hz), 4.98 (2H, s), 5.15 (2H, s),6.99 (2H, d, J=8.8 Hz), 7.07-7.12 (1H, m), 7.30-7.42 (6H, m), 7.58-7.65(3H, m).

Example 96

A mixture of benzyl bromide (0.209 ml), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassiumcarbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 15 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methyl E-4-(4-benzoloxybenzyloxyimino)-4-phenylbutyrate (400 mg,yield 62%) as a colorless oil from an ethyl acetate-hexane (1:7,v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.62 (3H, s), 5.07(2H, s), 5.15 (2H, s), 6.97 (2H, d, J=8.8 Hz), 7.30-7.46 (10H, m),7.60-7.66 (2H, m).

Example 97

Lithium hydroxide monohydrate (73.6 mg) was added to a solution ofmethylE-4-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyrate(430 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (1.8 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-4-[4-[5-methyl-2(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-4-phenylbutyricacid (366 mg, yield 88%) as colorless crystals. m.p. 142-143° C.

Example 98

Lithium hydroxide monohydrate (70.7 mg) was added to a solution ofmethyl E-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyrate (340 mg) intetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at roomtemperature for 2 hours. 1N hydrochloric acid (1.8 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-(4-benzyloxybenzyloxyimino)-4-phenylbutyric acid (238 mg, yield 72%)as colorless crystals. m.p. 86-87° C.

Example 99

A mixture of 2-chloromethylimidazo[1,2-α]pyridine (293 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassiumcarbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 17 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(321 mg, yield 45%) as a colorless oil from an ethyl acetate-hexane(3:2, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.59 (2H, m), 3.01-3.10 (2H, m), 3.62 (3H; s), 5.16(2H, s), 5.30 (2H, s), 6.78 (1H, dt, J=1.0, 6.8 Hz), 7.02 (2H, d, J=8.8Hz), 7.13-7.40 (7H, m), 7.56-7.66 (3H, m), 8.08 (1H, d, J=6.8 Hz).

Example 100

A mixture of 4-(chloromethyl)-2-phenyloxazole (250 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (369 mg), potassiumcarbonate (325 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 17 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (320mg, yield 58%) as a colorless oil from an ethyl acetate-hexane (2:9,v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.10(2H, s), 5.17 (2H, s), 7.01 (2H, d, J=8.8 Hz), 7.32-7.40 (5H, m),7.41-7.49 (3H, m), 7.60-7.66 (2H, m), 7.74 (1H, s), 8.03-8.09 (2H, m).

Example 101

Lithium hydroxide monohydrate (53.0 mg) was added to a solution ofmethylE-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyrate(280 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-4-[4-(imidazo[1,2-α]pyridin-2-ylmethoxy)benzyloxyimino]-4-phenylbutyricacid (206 mg, yield 76%) as colorless crystals. m.p. 180-182° C.

Example 102

Lithium hydroxide monohydrate (49.9 mg) was added to a solution ofmethylE-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (280mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirredat room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was addedto the reaction mixture and extracted with ethyl acetate. The ethylacetate layer was washed with an aqueous saturated solution of sodiumchloride, dried (MgSO₄) and concentrated. The residue was recrystallizedfrom ethyl acetate-hexane to obtainE-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid(237 mg, yield 87%) as colorless crystals. m.p. 144-145° C.

Example 103

A mixture of 2-chloromethylquinoline hydrochloride (488 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (650 mg), potassiumcarbonate (1.00 g) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 13 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyrate (655 mg,yield 70%) as a colorless oil from an ethyl acetate-hexane (1:4,v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.49-2.58 (2H, m), 3.01-3.10 (2H, m), 3.61 (3H, s), 5.15(2H, s), 5.40 (2H, s), 7.02 (2H, d, J=8.4 Hz), 7.31-7.38 (5H, m),7.50-7.85 (6H, m), 8.09 (1H, d, J=8.4 Hz), 8.19 (1H, d, J=8.4 Hz).

Example 104

Lithium hydroxide monohydrate (108 mg) was added to a solution of methylE-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyrate (585 mg) intetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at roomtemperature for 2 hours. 1N hydrochloric acid (2.6 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-4-phenyl-4-[4-(2-quinolinylmethoxy)benzyloxyimino]butyric acid (469mg, yield 83%) as colorless crystals. m.p. 133-134° C.

Example 105

A mixture of 4-(chloromethyl)-2-phenylthiazole (368 mg), methylE-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassiumcarbonate (442 mg) and N,N-dimethylformamide (10 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain methylE-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyrate(494 mg, yield 63%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 2.50-2.60 (2H, m), 3.02-3.11 (2H, m), 3.62 (3H, s), 5.17(2H, s), 5.28 (2H, s), 7.02 (2H, d, J=8.8 Hz), 7.31-7.49 (9H, m),7.59-7.65 (2H, m), 7.93-7.99 (2H, m).

Example 106

Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which wasstirred at room temperature for 30 minutes and concentrated. The residuewas dissolved in tetrahydrofuran (10 ml) and added dropwise to a mixtureof a 25% aqueous ammonia (15 ml) and ethyl acetate (20 ml) at 0° C.After stirred at room temperature for 1 hour, water was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The remaining crystals were recrystallized from ethylacetate to obtainE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyramide(315 mg, yield 45%) as colorless crystals. m.p. 164-165° C.

Example 107

Sodium methoxide (108 mg) was added to a solution ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (941 mg) in methanol (5 ml), which was stirred at room temperaturefor 1 hour and concentrated. The remaining crystals were recrystallizedfrom methanol-diethyl ether to obtain sodiumE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(456 mg, yield 46%) as colorless crystals. m.p. 64-70° C.

Example 108

Lithium hydroxide monohydrate (54.8 mg) was added to a solution ofmethylE-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyrate(424 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The remaining crystalswere recrystallized from ethyl acetate-hexane to obtainE-4-phenyl-4-[4-(2-phenyl-4-thiazolylmethoxy)benzyloxyimino]butyric acid(369 mg, yield 90%) as colorless crystals. m.p. 104-105° C.

Example 109

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), ethyl 2,2-dimethyl-3-oxo-3-phenylpropionate (468 mg), aceticacid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heatedto reflux for 5 days, the mixture was cooled to room temperature. Waterwas added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain ethylZ-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate(273 mg, yield 28%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.11 (3H, t, J=7.1 Hz), 1.31 (6H, s), 2.44 (3H, s), 3.96(2H, q, J=7.1 Hz), 5.00 (2H, s), 5.07 (2H, s), 7.00 (2H, d, J=8.6 Hz),7.26-7.46 (10H, m), 8.00-8.06 (2H, m).

Example 110

Potassium hydroxide (1.83 g) was added to a solution of ethylZ-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-3-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate(265 mg) in tetrahydrofuran (3 ml)-water (3 ml)-methanol (6 ml), themixture was heated to reflux for 3 days and cooled to room temperature.Dilute hydrochloric acid was added to the reaction mixture and extractedwith ethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The remaining crystals were recrystallized from ethyl acetate-hexane toobtainZ-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionicacid (130 mg, yield 52%) as pale-yellow crystals. m.p. 142-143° C.(decomposition).

Example 111

A mixture ofE-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-phenylpropionicacid (600 mg), 1-hydroxybenzotriazole ammonia complex (260 mg),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (328 mg) andN,N-dimethylformamide (5 ml) was stirred at room temperature for 15hours. Water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed successively with an aqueoussolution of potassium carbonate and an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The remaining crystalswere recrystallized from tetrahydrofuran-hexane to obtainE-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropanamide(512 mg, yield 86%) as colorless crystals. m.p. 164-165° C.

Example 112

Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which wasstirred at room temperature for 30 minutes and concentrated. The residuewas dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixtureof a 40% aqueous dimethylamine (20 ml) and ethyl acetate (20 ml) at 0°C. After stirred at room temperature for 2 hours, water was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtainE-N,N-dimethyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide(511 mg, yield 69%) as a colorless oil from an ethyl acetate-hexane(2:1, v/v).

NMR(CDCl₃) δ: 2.43-2.55 (5H, m), 2.83 (3H, s), 2.88 (3H, s), 3.01-3.10(2H, m), 5.00 (2H, s), 5.17 (2H, s), 7.01 (2H, d, J=8.6 Hz), 7.30-7.48(8H, m), 7.63-7.71 (2H, m), 7.97-8.05 (2H, m).

Example 113

Oxalyl chloride (0.156 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (700 mg) in tetrahydrofuran (10 ml) at room temperature, which wasstirred at room temperature for 30 minutes and concentrated. The residuewas dissolved in tetrahydrofuran (5 ml) and added dropwise to a mixtureof a 40% aqueous methylamine (20 ml) and ethyl acetate (30 ml) at 0° C.After stirred at room temperature for 1 hour, water was added andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The remaining crystals were recrystallized from ethylacetate-hexane to obtainE-N-methyl-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutaneamide(466 mg, yield 65%) as colorless crystals. m.p. 141-142° C.

Example 114

Lithium hydroxide monohydrate (44.6mg) was added to a solution ofE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (500 mg) in methanol (10 ml), which was stirred at room temperaturefor 30 minutes and concentrated. The remaining crystals wererecrystallized from methanol-diethyl ether to obtain lithiumE-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(485 mg, yield 96%) as colorless crystals. m.p. 201-203° C.

Example 115

A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added toa solution of ethylE-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoate(730 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at roomtemperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to thereaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was recrystallized fromethyl acetate-hexane to obtainE-7-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-7-phenylheptanoicacid (569 mg, yield 82%) as colorless crystals. m.p. 84-85° C.

Example 116

Lithium hydroxide monohydrate (159 mg) was added to a solution of ethylZ-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate(340 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 1 hour. 1N hydrochloric acid (3.8 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainZ-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoicacid (293 mg, yield 91%) as colorless crystals. m.p. 88-89° C.

Example 117

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), methyl 8-(4-methoxyphenyl)-8-oxooctanoate (538 mg), aceticacid (0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heatedto reflux for 16 hours, the mixture was cooled to room temperature.Water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain methylE-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(650 mg, yield 59%) as a colorless oil from an ethyl acetate-hexane(2:7, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J=7.5 Hz), 2.44 (3H, s),2.72 (2H, t, J=7.7 Hz), 3.65 (3H, s), 3.82 (3H, s), 5.00 (2H, s), 5.13(2H, s), 6.88 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=8.8 Hz), 7.35 (2H, d,J=8.8 Hz), 7.39-7.48 (3H, m), 7.56 (2H, d, J=8.8 Hz), 7.99-8.05 (2H, m).

Example 118

Lithium hydroxide monohydrate (128 mg) was added to a solution of methylE-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(580 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 1 hour. 1N hydrochloric acid (3.1 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-(4-methoxyphenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoicacid (528 mg, yield 93%) as colorless crystals. m.p. 69-70° C.

Example 119

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), 8-(4-chlorophenyl)-8-oxooctanoic acid (546 mg), acetic acid(0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated toreflux for 18 hours, the mixture was cooled to room temperature. Waterwas added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain methylE-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(828 mg, yield 75%) as a colorless oil from an ethyl acetate-hexane(1:6, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J=7.5 Hz), 2.44 (3H, s),2.67-2.76 (2H, m), 3.65 (3H, s), 5.00 (2H, s), 5.14 (2H, s), 7.01 (2H,d, J=8.8 Hz), 7.29-7.37 (4H, m), 7.40-7.47 (3H, m), 7.55 (2H, d, J=8.8Hz), 7.99-8.05 (2H, m).

Example 120

MethylZ-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(215 mg, yield 19%) as a colorless oil was obtained from a fractionwhich eluted following the E-compound in Example 119.

NMR(CDCl₃) δ: 1.20-1.65 (8H, m), 2.27 (2H, t, J=7.4 Hz), 2.41-2.53 (5H,m), 3.65 (3H, s), 4.99 (2H, s), 5.01 (2H, s), 6.98 (2H, d, J=8.8 Hz),7.22-7.37 (6H, m), 7.40-7.46 (3H, m), 7.99-8.05 (2H, m).

Example 121

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(600 mg), 8-(4-fluorophenyl)-8-oxooctanoic acid (514 mg), acetic acid(0.331 ml), sodium acetate (317 mg) and methanol (20 ml) was heated toreflux for 18 hours, the mixture was cooled to room temperature. Waterwas added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wassubjected to silica gel chromatography to obtain methylE-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(771 mg, yield 71%) as a colorless oil from an ethyl acetate-hexane(1:6, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (8H, m), 2.26 (2H, t, J=7.5 Hz), 2.44 (3H, s),2.68-2.76 (2H, m), 3.65 (3H, s), 5.00 (2H, s), 5.14 (2H, s), 6.97-7.10(4H, m), 7.35 (2H, d, J=8.8 Hz), 7.39-7.48 (3H, m), 7.54-7.63 (2H, m),7.97-8.05 (2H, m).

Example 122

MethylZ-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(205 mg, yield 19%) as a colorless oil was obtained from a fractionwhich eluted following the E-compound in Example 121.

NMR(CDCl₃) δ: 1.20-1.65 (8H, m), 2.27 (2H, t, J=7.5 Hz), 2.43 (3H, s),2.45-2.53 (2H, m), 3.65 (3H, s), 4.99 (2H, s), 5.01 (2H, s), 6.95-7.09(4H, m), 7.23-7.46 (7H, m), 7.98-8.04 (2H, m).

Example 123

Lithium hydroxide monohydrate (160 mg) was added to a solution of methylE-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(730 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 3 hours. 1N hydrochloric acid (3.9 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoicacid (632 mg, yield 89%) as colorless crystals. m.p. 90-91° C.

Example 124

Lithium hydroxide monohydrate (43.7 mg) was added to a solution ofmethylZ-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(200 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainZ-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoicacid (169 mg, yield 87%) as colorless crystals. m.p. 54-57° C.

Example 125

Lithium hydroxide monohydrate (157 mg) was added to a solution of methylE-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(700 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 3 hours. 1N hydrochloric acid (3.8 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoicacid (608 mg, yield 89%) as colorless crystals. m.p. 79-80° C.

Example 126

Lithium hydroxide monohydrate (42.8 mg) was added to a solution ofmethylZ-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate(190 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) andstirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainZ-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoicacid (59 mg, yield 32%) as colorless crystals. m.p. 56-57° C.

Example 127

A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (335 mg), ethylE-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg), potassiumcarbonate (432 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoate(267 mg, yield 32%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.20-1.65 (11H, m), 2.24 (2H, t, J=7.5 Hz), 2.70-2.79 (2H,m), 4.11 (2H, q, J=7.1 Hz), 5.15 (2H, s), 5.26 (2H, s), 7.05 (2H, d,J=8.8 Hz), 7.30-7.40 (5H, m), 7.48-7.66 (5H, m), 8.17 (2H, d, J=8.2 Hz).

Example 128

Lithium hydroxide monohydrate (54.9 mg) was added to a solution of ethylE-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoate(236 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (1.4 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-phenyl-8-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]octanoicacid (208 mg, yield 93%) as colorless crystals. m.p. 76-77° C.

Example 129

Lithium hydroxide monohydrate (143 mg) was added to a solution of ethylE-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate(618 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (3.5 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoicacid (523 mg, yield 90%) as colorless crystals. m.p. 75-77° C.

Example 130

Lithium hydroxide monohydrate (153 mg) was added to a solution of ethylE-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctane(682 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (3.7 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-8-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoicacid (567 mg, yield 87%) as colorless crystals. m.p. 106-108° C.

Example 131

A mixture of 4-chloromethyl-2-(2-furyl)-5-methyloxazole (368 mg), ethylE-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassiumcarbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 13 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate(770 mg, yield 88%) as a colorless oil from an ethyl acetate-hexane(2:7, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t,J=7.1 Hz), 2.42 (3H, s), 2.73-2.82 (2H, m), 4.09 (2H, q, J=7.1 Hz), 5.00(2H, s), 5.15 (2H, s), 6.51-6.54 (1H, m), 6.95-7.03 (3H, m), 7.30-7.39(5H, m), 7.53-7.64 (3H, m).

Example 132

Lithium hydroxide monohydrate (163 mg) was added to a solution of ethylE-6-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate(670 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (3.9 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-6-[4-[2-(2-furyl)-5methyl-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoicacid (625 mg, yield 98%) as colorless crystals. m.p. 112-113° C.

Example 133

A mixture of 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (397 g), ethylE-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassiumcarbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate(856 mg, yield 95%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t,J=7.1 Hz), 2.41 (3H, s), 2.77 (2H, t, J=7.4 Hz), 4.09 (2H, q, J=7.1 Hz),4.98 (2H, s), 5.15 (2H, s), 6.99 (2H, d, J=8.8 Hz), 7.09 (1H, dd, J=3.6,5.0 Hz), 7.31-7.42 (6H, m), 7.58-7.65 (3H, m).

Example 134

A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (362 mg), ethylE-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassiumcarbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoate(649 mg, yield 75%) as a colorless oil from an ethyl acetate-hexane(1:4, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t,J=7.2 Hz), 2.77 (2H, t, J=7.5 Hz), 4.09 (2H, q, J=7.1 Hz), 5.16 (2H, s),5.27 (2H, s), 7.06 (2H, d, J=8.8 Hz), 7.31-7.40 (5H, m), 7.49-7.66 (5H,m), 8.14-8.20 (2H, m).

Example 135

Lithium hydroxide monohydrate (177 mg) was added to a solution of ethylE-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate(747 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (4.3 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoicacid (653 mg, yield 92%) as colorless crystals. m.p. 101-102° C.

Example 136

Lithium hydroxide monohydrate (134 mg) was added to a solution of ethylE-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoate(545 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (3.3 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-6-phenyl-6-[4-(5-phenyl-1,2,4-oxadiazol-3-ylmethoxy)benzyloxyimino]hexanoicacid (465 mg, yield 90%) as colorless crystals. m.p. 88-89° C.

Example 137

A mixture of 5-chloromethyl-3-phenyl-1,2,4-oxadiazole (362 mg), ethylE-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassiumcarbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at roomtemperature for 18 hours. Water was added to the reaction mixture andextracted with ethyl acetate. The ethyl acetate layer was washed with anaqueous saturated solution of sodium chloride, dried (MgSO₄) andconcentrated. The residue was subjected to silica gel chromatography toobtain ethylE-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoate(789 mg, yield 92%) as a colorless oil from an ethyl acetate-hexane(2:9, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 1.45-1.75 (4H, m), 2.28 (2H, t,J=7.4 Hz), 2.77 (2H, t, J=7.4 Hz), 4.09 (2H, q, J=7.1 Hz), 5.16 (2H, s),5.36 (2H, s), 7.02 (2H, d, J=8.6 Hz), 7.28-7.65 (10H, m), 8.06-8.15 (2H,m).

Example 138

Lithium hydroxide monohydrate (194 mg) was added to a solution of ethylE-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoate(790 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) andstirred at room temperature for 4 hours. 1N hydrochloric acid (4.7 ml)was added to the reaction mixture and extracted with ethyl acetate. Theethyl acetate layer was washed with an aqueous saturated solution ofsodium chloride, dried (MgSO₄) and concentrated. The residue wasrecrystallized from ethyl acetate-hexane to obtainE-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoicacid (637 mg, yield 85%) as colorless crystals. m.p. 91-92° C.

Example 139

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(1.00 g), 4-oxo-4-phenylbutanamide (571 mg), acetic acid (0.553 ml),sodium acetate (528 mg) and ethanol (20 ml) was heated to reflux for 10hours, the mixture was cooled to room temperature. Water was added tothe reaction mixture and extracted with ethyl acetate. The ethyl acetatelayer was washed with an aqueous saturated solution of sodium chloride,dried (MgSO₄) and concentrated. The residue was subjected to silica gelchromatography and concentrated a portion from an ethyl acetate-hexane(3:1, v/v)-eluted fraction which eluted following the E-compound, toobtain crystals. The crystals were recrystallized from ethanol to obtainZ-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutanamide(120 mg, yield 8%) as colorless crystals. m.p. 110-112° C.

Example 140

After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine(467 mg), methyl 2,2-dimethyl-6-oxo-6-phenylhexanoate (340 mg), aceticacid (0.259 ml), sodium acetate (248 mg) and methanol (15 ml) was heatedto reflux for 15 hours, the mixture was cooled to room temperature.Water was added to the reaction mixture and extracted with ethylacetate. The ethyl acetate layer was washed with an aqueous saturatedsolution of sodium chloride, dried (MgSO₄) and concentrated. The residuewas subjected to silica gel chromatography to obtain methylE-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(348 mg, yield 47%) as a colorless oil from an ethyl acetate-hexane(1:5, v/v)-eluted fraction.

NMR(CDCl₃) δ: 1.10 (6H, s), 1.35-1.65 (4H, m), 2.44 (3H, s), 2.73 (2H,t, J=7.3 Hz), 3.55 (3H, s), 5.00 (2H, s), 5.15 (2H, s), 7.02 (2H, d,J=8.8 Hz), 7.33-7.48 (8H, m), 7.57-7.63 (2H, m), 7.99-8.05 (2H, m).

Example 141

A 4N aqueous solution of potassium hydroxide (5 ml) was added to asolution of methylE-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(340 mg) in tetrahydrofuran (5 ml)-methanol (5 ml), which was heated toreflux for 2 hours and cooled to room temperature. Dilute hydrochloricacid was added to the reaction mixture to neutralize and extracted withethyl acetate. The ethyl acetate layer was washed with an aqueoussaturated solution of sodium chloride, dried (MgSO₄) and concentrated.The residue was subjected to silica gel chromatography to obtainE-2,2-dimethyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoicacid (275 mg, yield 83%) as colorless crystals. m.p. 111-112° C.

Example 142

Oxalyl chloride (0.126 ml) and N,N-dimethylformamide (catalytic amount)were added to a solution ofE-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanoate(600 mg) in tetrahydrofuran (5 ml) at room temperature, which wasstirred at room temperature for 30 minutes and concentrated. The residuewas dissolved in tetrahydrofuran (10 ml) and methanesulfonamide (137 mg)and N,N-dimethylaminopyridine (293 mg) were added. After the reactionmixture was stirred at room temperature for 18 hours, 1N hydrochloricacid was added and extracted with ethyl acetate. The ethyl acetate layerwas washed with an aqueous saturated solution of sodium chloride, dried(MgSO₄) and concentrated. The residue was subjected to silica gelchromatography to obtain crystals from an ethyl acetate-hexane (1:1,v/v)-eluted fraction. The crystals were recrystallized from ethylacetate-hexane to obtainE-N-methanesulfonyl-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanamide(458 mg, yield 66%) as colorless crystals. m.p. 130-132° C.

Example 143

To a stirred solution of4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.50 g) andmethyl E-4-hydroxyimino-4-phenylbutyrate (990 mg) inN,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 200mg) at 0° C. After stirring for 2 hours, the reaction mixture was pouredinto water, neutralized with 2N hydrochloric acid, and extracted withethyl acetate. The extract was washed with water, dried (MgSO₄), andconcentrated. The residue was purified by column chromatography onsilica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methylE-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.65 g, yield 71%) as a colorless oil.

NMR(CDCl₃) δ: 2.43 (3H, s), 2.5-2.65 (2H, m), 3.0-3.15 (2H, m), 3.61(3H, s), 5.07 (2H, s), 5.33 (2H, s), 6.98 (1H, dd, J=7.5, 1.0 Hz),7.25-7.5 (8H, m), 7.55-7.7 (2H, m), 7.95-8.1 (2H, m).

Example 144

A mixture of methylE-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.60 g), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodiumhydroxide (5 ml) was stirred at room temperature for 2 hours. Thereaction mixture was poured into water, acidified with 2N hydrochloricacid, and extracted with ethyl acetate. The extract was washed withwater, dried (MgSO₄), and concentrated to giveE-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (1.42 g, yield 91%) as crystals. Recrystallization from ethylacetate-hexane gave colorless needles. m.p. 116-117° C.

Example 145

To a stirred solution of4-(4-chloromethyl-2,6-dimethoxyphenoxymethyl)-5-methyl-2-phenyloxazole(1.00 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (585 mg) inN,N-dimethylformamide (40 ml) was added sodium hydride (60% in oil, 115mg) at 0° C. After stirring for 2 hours, the reaction mixture was pouredinto water, neutralized with 2N hydrochloric acid, and extracted withethyl acetate. The extract was washed with water, dried (MgSO₄), andconcentrated. The residue was purified by column chromatography onsilica gel. Elution with ethyl acetate-hexane (1:3, v/v) gave methylE-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(970 mg, yield 65%) as a colorless oil.

NMR(CDCl₃) δ: 2.32 (3H, s), 2.5-2.65 (2H, m), 3.05-3.15 (2H, m), 3.63(3H, s), 3.84 (6H, s), 4.97 (2H, s), 5.16 (2H, s), 6.63 (2H, s), 7.3-7.5(6H, m), 7.6-7.7 (2H, m), 7.95-8.05 (2H, m).

Example 146

A mixture of methylE-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(970 mg), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodiumhydroxide (5 ml) was stirred at room temperature for 1 hour. Thereaction mixture was poured into water, acidified with 2N hydrochloricacid, and extracted with ethyl acetate. The extract was washed withwater, dried (MgSO₄), and concentrated to giveE-4-[3,5-dimethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (880 mg, yield 93%) as crystals. Recrystallization from ethylacetate-isopropyl ether gave colorless needles. m.p. 8990° C.

Example 147

To a stirred solution of4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole(1.65 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (1.04 g) inN,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 200mg) at 0° C. After stirring for 1 hour, the reaction mixture was pouredinto water, neutralized with 1N hydrochloric acid, and extracted withethyl acetate. The extract was washed with water, dried (MgSO₄), andconcentrated. The residue was purified by column chromatography onsilica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methylE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate(1.60 g, yield 64%) as crystals. Recrystallization from ethylacetate-hexane gave pale-yellow prisms. m.p. 67-69° C.

Example 148

A mixture of methylE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate(1.55 g, ethanol (10 ml) and 1N aqueous sodium hydroxide (5 ml) wasstirred at room temperature for 2 hours. The reaction mixture was pouredinto water and acidified with 1N hydrochloric acid to giveE-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyricacid as crystals (1.40 g, yield 93%). Recrystallization fromethanol-isopropyl ether gave colorless prisms. m.p. 131-132 ° C.

Example 149

In substantially the same manner as in example 147,4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole wasreacted with E-4-hydroxyimino-4-phenylbutyrate (1.10 g) to obtain methylE-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.20 g, yield 44%) as crystals. Recrystallization from ethylacetate-isopropyl ether gave pale-yellow prisms. m.p. 112-114° C.

Example 150

In substantially the same manner as in example 148, methylE-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate(1.00 g) was reacted with 1N aqueous sodium hydroxide to obtainE-4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid (790 mg, yield 80%). Recrystallization from ethanol-isopropyl ethergave colorless prisms. m.p. 134-135° C.

Pharmaceutical Composition Example 1 (Production of Capsules)

1) compound (7) 30 mg 2) cellulose powder 10 mg 3) lactose 19 mg 4)magnesium stearic acid  1 mg Sum 60 mg

Components 1), 2), 3) and 4) are mixed and packed in gelatin capsules.

Pharmaceutical Composition Example 2 (Production of Tablets)

1) compound (7) 30 g 2) lactose 50 g 3) corn starch 15 g 4)carboxymethylcellulose calcium 44 g 5) magnesium stearic acid  1 g 1000tablets  Sum 140 g 

The entire amounts of Components 1), 2) and 3) and 30 g of Component 4)are milled with water, freeze-dried, and then pulverized. The pulverizedpowder is admixed with 14 g of Component 4) and 1 g of Component 5), andcompacted into tablets. In this manner, 1000 tablets each of whichcontaining 30 mg of compound (7) are produced.

Effects of the Invention

A compound or a pharmaceutical composition according to the presentinvention has less toxicity, and can be used for the prevention ortreatment of diabetes mellitus (e.g., insulin-dependent diabetesmellitus (type-1 diabetes mellitus), non-insulin-dependent diabetesmellitus (type-2 diabetes mellitus), pregnancy diabetes mellitus and thelike), hyperlipemia (e.g., hypertriglycemia, hypercholesterolemia,hypoHDLemia and the like), insulin insensitivity, insulin resistance,and impaired glucose tolerance (IGT).

A compound or a pharmaceutical composition according to the presentinvention may also be used for the prevention or treatment of diabeticcomplications (e.g., neuropathy, nephropathy, retinopathy, cataract,microangiopathy, osteopenia and the like), obesity, osteoporosis,cachexia (e.g., carcinomatous cachexia, tuberculous cachexia, diabeticcachexia, hemophathic cachexia, endocrinopathic cachexia, infectiouscachexia or cachexia induced by acquired immunodeficiency syndrome),fatty liver, hypertension, polycystic ovary syndrome, renal disorders(e.g., glomerular nephritis, glomerulosclerosis, nephrotic syndrome,hypertensive nephrosclerosis, terminal renal disorders and the like),muscular dystrophy, myocardiac infarction, angina pectoris, cerebralinfarction, insulin resistance syndrome, syndrome X,hyperinsulinemia-induced sensory disorder, tumors (e.g., leukemia,breast cancer, prostate cancer, skin cancer and the like), inflammatorydiseases (e.g., rheumatoid arthritis, spondylitis deformans,osteoarthritis, lumbago, gout, surgical wound inflammation and swellingremedy, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia,pancreatitis and the like), arterial sclerosis (e.g., atherosclerosisand the like).

A compound according to the invention may also be employed as apharmaceutical for controlling appetite or food intake, diet andanorexia.

What is claimed is:
 1. A compound represented by Formula (I):

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 2. A compound of claim 1 wherein X is a bond or a grouprepresented by —NR⁶— wherein R⁶ is an optionally substituted alkylgroup.
 3. A compound of claim 1 wherein n is 1 or
 2. 4. A compound ofclaim 1 wherein Y is an oxygen atom.
 5. A compound of claim 1 wherein pis an integer of 1 to
 3. 6. A compound of claim 1 wherein R³ is ahydroxy group or —OR⁸ or —NR^(9′)R^(10′), wherein R⁸ is an optionallysubstituted hydrocarbon group and R^(9′) and R^(10′) are the same ordifferent groups which are selected from a hydrogen atom, an optionallysubstituted hydrocarbon group, or R^(9′) and R^(10′) combine together toform a ring.
 7. A compound of claim 1 wherein q is an integer of 0 to 4.8. A compound of claim 1 wherein R² an optionally substitutedhydrocarbon group.
 9. A compound of claim 1 wherein said thiazolyl groupoptionally has one or two substituents which are selected from the groupof an optionally substituted phenyl, an optionally substituted furyl, anoptionally substituted thienyl and an optionally substituted C₁₋₄ alkyl.10. A pharmaceutical composition comprising a compound represented bythe formula of

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof; and a pharmacologically acceptable carrier.
 11. A methodfor treating diabetes mellitus which comprises administering apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 12. A method for treating hyperlipemia which comprisesadministering a pharmaceutically effective amount of the compoundrepresented by the formula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 13. A method for improving an insulin resistance whichcomprises administering a pharmaceutically effective amount of thecompound represented by the formula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 14. A method for treating impaired glucose tolerance whichcomprises administering a pharmaceutically effective amount of thecompound represented by the formula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same of differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; orsalt thereof.
 15. A method for treating an inflammatory disease whichcomprises administering a pharmaceutically effective amount of thecompound represented by the formula of:

wherein R¹ is an optionally substituted thiazoyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom of an optionally substituted alkyl group; n is an interger of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 16. A method for treating arterial sclerosis whichcomprises administering a pharmaceutically effective amount of thecompound represented by the formula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 17. A method of making a medicament for treating diabetesmellitus, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 18. A method of making a medicament for treatinghyperlipemia, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 19. A method for making a medicament for improving aninsulin resistance, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 20. A method for making a medicament for treating impairedglucose tolerance, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 21. A method for making a medicament for treating aninflammatory disease, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.
 22. A method for making a medicament for treating arterialsclerosis, which comprises formulating the medicament with apharmaceutically effective amount of the compound represented by theformula of:

wherein R¹ is an optionally substituted thiazolyl group; X is a bond,—CO—, —CH(OH)— or a group represented by —NR⁶— wherein R⁶ is a hydrogenatom or an optionally substituted alkyl group; n is an integer of 1 to3; Y is an oxygen atom, a sulfur atom, —SO—, —SO₂— or a grouprepresented by —NR⁷— wherein R⁷ is a hydrogen atom or an optionallysubstituted alkyl group; ring A is a benzene ring optionally havingadditional one to three substituents; p is an integer of 1 to 8; R² is ahydrogen atom, an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group; q is an integer of 0 to 6; mis 0 or 1; R³ is a hydroxy group; OR⁸, wherein R⁸ is an optionallysubstituted hydrocarbon group; or NR⁹R¹⁰, wherein R⁹ and R¹⁰ are thesame or different groups which are selected from a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedheterocyclic group and an optionally substituted acyl group or R⁹ andR¹⁰ combine together to form a ring; R⁴ and R⁵ are the same or differentgroups which are selected from a hydrogen atom and an optionallysubstituted hydrocarbon group wherein R⁴ may form a ring with R²; or asalt thereof.